Furoisoquinoline derivatives, process for producing the same and use thereof

ABSTRACT

A compound having a partial structure represented by Formula:  
                 
 
     or a salt thereof has an excellent phosphodiesterase (PDE) IV-inhibiting effect, and is useful as a prophylactic or therapeutic agent against inflammatory diseases, for example, bronchial asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, autoimmune disease, diabetes and the like.

TECHNICAL FIELD

[0001] The present invention relates to a novel furoisoquinolinederivative which has a phosphodiesterase (PDE) IV-inhibiting effect andwhich is useful as a prophylactic or therapeutic agent against theinflammatory diseases, for example, bronchial asthma, chronicobstructive pulmonary disease (COPD), rheumatoid arthritis, autoimmunedisease, diabetes and the like and process for producing the same anduse thereof.

BACKGROUND ART

[0002] It is known in these days that a large number of hormones andneurotransmitters function to increase or decrease the intracellularlevel of cyclic adenosine-3′,5′-monophosphate (cAMP) which is anintracellular second messenger, whereby regulating the cellularfunctions. The intracellular cAMP level is regulated by synthesizing anddegradating enzymes. Thus, cAMP is produced by adenyl cyclases anddegradated by phosphodiesterase (PDE). These degradating enzymes alsoregulate the degradation of cyclic guanosine-3′,5′-monophosphate.

[0003] Seven isozymes of the PDE have been found so far [PhysiologicalReviews, Vol.75, p725 (1995), Endocrine Reviews, Vol.16, p370, (1995)],and each functions, in various cells such as those in central nervoussystem, circulatory organs, respiratory organs, digestive organs,genital organs, blood cells and tracheal smooth muscles, to regulateintracellular cAMP and cGMP levels, whereby controlling the cellularfunctions. It is also known that in an inflammatory cell such as aneosinophile, neutrophile, monocyte, T-lymphocyte and macrophage a PDEisozyme referred to as PDE type-IV exists predominantly [Clinical andExperimental Allergy, Vol.22, p337 (1992)].

[0004] Pharmaceuticals, which can broadly be classified into threegroups, are employed as therapeutic agents against a bronchial asthma.Thus, the three types including bronchodilators (for example,β-adrenaline receptor agonists), antiinflammatory agents (for example,corticosteroids) and xanthine derivatives having both of thebronchodilating effect and antiinflammatory effect (for example,theophylline) are employed. Among these, theophylline has been employedas a therapeutic agent against asthma for a long time. Theophylline isbecoming more interesting in these days since its bronchodilating effecthas been found to be derived from a PDE-inhibiting effect. However,theophylline is a non-selective PDE inhibitor and sometimes exhibits acardiovascular side effect. Then, its blood level should strictly becontrolled to reduce the side effect. Accordingly, a medicament fortreating an inflammatory disease such as asthma which inhibits the PDEtype-VI selectively and which has no effects on other isozymes of thePDE is desired.

[0005] A study indicating a possibility that a PDE type-IV-selectiveinhibitor is an effective therapeutic agent against an inflammatorydisease such as asthma was reported [Pulmonary Pharmacology, Vol.7, p1(1994)]. Thus, it was suggested that a PDE type-IV-selective inhibitorhas the both of an antiinflammatory effect and a bronchodilating effectand may exhibit a therapeutic effect on an inflammatory disease such asasthma. In fact, compounds having inhibitory effects selectively on thePDE type-IV are subjected currently to an extensive development all overthe world. For example, rolipram (JP-A-50-157360) having the structurerepresented by Formula:

[0006] and SB 207499 [The Journal of Pharmacology and ExperimentalTherapeutics, Vol.287, p988 (1998), Journal of Medicinal Chemistry,Vol.41, p821 (1998)] represented by Formula:

[0007] are under development. However, any of those listed above has notbeen employed clinically, and a further useful agent is desired to bedeveloped.

[0008] On the other hand, a method for synthesizing a compoundrepresented by Formula:

[0009] is disclosed in Indian Journal of Chemistry, Section B, Vol.31B,p578 (1992).

[0010] Moreover, an antibacterial compound represented by Formula:

[0011] is also disclosed in Indian Journal of Chemistry, Section B,Vol.33B, p552 (1994).

[0012] A potent selective PDE type-IV inhibitor having a novel chemicalstructure is expected to have a sufficient prophylactic or therapeuticeffect in a wide range of diseases accompanied with inflammations, andis desired to be developed. The objective of the invention is to providenovel heterocyclic compounds which have selective PDE type-IV-inhibitingeffect and increase the intracellular cAMP level whereby exhibitingbronchodilating and antiinflammatory effects and which is also excellentin terms of the safety.

SUMMARY OF THE INVENTION

[0013] We made an effort and were finally successful for the first timein synthesizing a novel furoisoquinoline derivative (hereinafterabbreviated sometimes as Compound (I)) having a partial structurerepresented by Formula:

[0014] (wherein each of Ring A, Ring B and Ring C may have substituents,especially a novel furoisoquinoline derivative (hereinafter abbreviatedsometimes as Compound (I′)) whose significant chemical structuralcharacteristics are the substituents introduced in the 1-, 2-, 3-, 4-,5-, 6-, 8-, 9-positions etc. on the furoisoquinoline backbone,represented by Formula:

[0015] (wherein R¹ is a hydrogen atom, optionally substitutedhydrocarbon group, optionally substituted heterocyclic group oroptionally substituted amino group, each of R² and R³ is a hydrogenatom, optionally substituted hydrocarbon group or acyl group, and R² andR³ may be taken together with the adjacent carbon atom to form anoptionally substituted 3- to 8-membered ring, R⁴ is a hydrogen atom,cyano group, optionally substituted hydrocarbon group, acyl group oroptionally substituted hydroxy group, R⁵ is (1) a hydrogen atom, (2) anoptionally substituted hydrocarbon group, (3) an acyl group, (4) anoptionally substituted heterocyclic group or (5) a halogen atom, each ofR⁶ and R⁷ is a hydrogen atom or optionally substituted hydrocarbongroup, and R⁶ and R⁷ are taken together with the adjacent carbon atom toform an optionally substituted 3- to 8-membered ring, each of R⁸ and R⁹is a hydrogen atom or optionally substituted hydrocarbon group, X is abond, oxygen atom, optionally oxidized sulfur atom or optionallysubstituted nitrogen atom, Y is an optionally substituted methylenegroup or carbonyl group and n is 0 to 1), or a salt, prodrug or hydratethereof, and discovered that such a compound has, on the basis of itsspecific chemical structure, an unexpectedly excellent phosphodiesterase(PDE) IV-inhibiting effect, and can be used as a prophylactic ortherapeutic agent against an inflammation-induced disease, for example,bronchial asthma, chronic obstructive pulmonary disease (COPD),rheumatoid arthritis, autoimmune disease, diabetes and the like. We madea further effort based on these findings, and finally established thepresent invention.

[0016] Thus, the invention provides:

[0017] [1] a compound having a partial structure represented by Formula:

[0018] or its salt,

[0019] [2] the compound according to the above-mentioned [1] representedby Formula:

[0020] (wherein R¹ is a hydrogen atom, optionally substitutedhydrocarbon group, optionally substituted heterocyclic group oroptionally substituted amino group,

[0021] each of R² and R³ is a hydrogen atom, optionally substitutedhydrocarbon group or acyl group, and R² and R³ may be taken togetherwith the adjacent carbon atom to form an optionally substituted 3- to8-membered ring,

[0022] R⁴ is a hydrogen atom, cyano group, optionally substitutedhydrocarbon group, acyl group or optionally substituted hydroxy group,

[0023] R⁵ is (1) a hydrogen atom, (2) an optionally substitutedhydrocarbon group, (3) an acyl group, (4) an optionally substitutedheterocyclic group or (5) a halogen atom,

[0024] each of R⁶ and R⁷ is a hydrogen atom or optionally substitutedhydrocarbon group, and R⁶ and R⁷ are taken together with the adjacentcarbon atom to form an optionally substituted 3- to 8-membered ring,

[0025] each of R⁸ and R⁹ is a hydrogen atom or optionally substitutedhydrocarbon group,

[0026] X is a bond, oxygen atom, optionally oxidized sulfur atom oroptionally substituted nitrogen atom,

[0027] Y is an optionally substituted methylene group or carbonyl group,

[0028] and n is 0 to 1),

[0029] [3] the compound according to the above-mentioned [2] whereineach of R² and R³ is a hydrogen atom, optionally substituted hydrocarbongroup or acyl group, R² and R³ are taken together with the adjacentcarbon atom to form an optionally substituted 3- to 8-memberedhomocyclic or heterocyclic group, R⁴ is a hydrogen atom or optionallysubstituted hydrocarbon group, each of R⁶ and R⁷ is a hydrogen atom oroptionally substituted hydrocarbon group, R⁶ and R⁷ may be takentogether with the adjacent carbon atom to form an optionally substituted3- to 8-membered homocyclic group, Y is methylene group which may have ahydroxy group or carbonyl group,

[0030] [4] the compound according to the above-mentioned [2] wherein:

[0031] R¹ is any of the following (i) to (iii):

[0032] (i) a C₁₆ alkyl group, C₂-₆ alkenyl group, C₂-₆ alkynyl group,C₃₋₆ cycloalkyl group, C₃₋₆ cycloalkenyl group, C₆₋₁₄ aryl group orC₇₋₁₆ aralkyl group which may have 1 to 5 substituent(s) selected fromthe group (hereinafter referred to as Substituent Group A) consisting of(1) a halogen atom, (2) a C₁₋₃ alkylenedioxy group, (3) a nitro group,(4) a cyano group, (5) an optionally halogenated C₁₋₆ alkyl group, (6)an optionally halogenated C₂₋₆ alkenyl group, (7) an optionallyhalogenated C₂₋₆ alkynyl group, (8) a C₃₋₆ cycloalkyl group, (9) a C₆₋₁₄aryl group, (10) an optionally halogenated C₁₆ alkoxy group, (11) anoptionally halogenated C₁₋₆ alkylthio group, (12) a hydroxy group, (13)an amino group, (14) a mono-C₁₋₆ alkylamino group, (15) a mono-C₆₋₁₄arylamino group, (16) a di-C₁₋₆ alkylamino group, (17) a di-C₆₋₁₄arylamino group, (18) an acyl group selected from formyl, carboxy,carbamoyl, C₁₋₆ alkyl-carbonyl, C₃₋₆ cycloalkyl-carbonyl, C₁₋₆alkoxy-carbonyl, C₆₋₁₄ aryl-carbonyl, C₇₋₁₆ aralkyl-carbonyl, C₆₋₁₄aryloxy-carbonyl, C₇₋₁₆ aralkyloxy-carbonyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-carbonyl, mono-C₁₋₆alkyl-carbamoyl, di-C₁₋₆ alkyl-carbamoyl, C₆₋₁₄ aryl-carbamoyl, (5- or6-membered heterocycle having, in addition to carbon atoms, 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygenatoms)-carbamoyl, C₁₋₆ alkyl-thiocarbonyl, C₃₋₆ cycloalkyl-thiocarbonyl,C₁₋₆ alkoxy-thiocarbonyl, C₆₋₁₄ aryl-thiocarbonyl, C₇₋₁₆aralkyl-thiocarbonyl, C₆₋₁₄ aryloxy-thiocarbonyl, C₇₋₁₆aralkyloxy-thiocarbonyl, (5- or 6-membered heterocycle having, inaddition to carbon atoms, 1 to 3 heteroatom(s) selected from nitrogen,sulfur and oxygen atoms)-thiocarbonyl, thiocarbamoyl, mono-C₁₋₆alkyl-thiocarbamoyl, di-C₁₋₆ alkyl-thiocarbamoyl, C₆₋₁₄aryl-thiocarbamoyl, (5- or 6-membered heterocycle having, in addition tocarbon atoms, 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms)-thiocarbamoyl, mono-C₁₋₆ alkylsulfamoyl, di-C₁₋₆alkylsulfamoyl, C₆₋₁₄ arylsulfamoyl, C₁₋₆ alkylsulfonyl, C₆₋₁₄arylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₄ arylsulfinyl, sulfino, sulfo,C₁₋₆ alkoxysulfinyl, C₆₋₁₄ aryloxysulfinyl, C₁₋₆ alkoxysulfonyl andC₆₋₁₄ aryloxysulfonyl, (19) an acylamino group selected fromformylamino, C₁₋₆ alkyl-carboxamido, C₆₋₁₄ aryl-carboxamido, C₁₋₆alkoxy-carboxamido, C₁₋₆ alkylsulfonylamino and C₆₋₁₄ arylsulfonylamino,(20) an acyloxy group selected from C₁₋₆ alkyl-carbonyloxy, C₆₋₁₄aryl-carbonyloxy, C₁₋₆ alkoxy-carbonyloxy, mono-C₁₋₆ alkyl-arbamoyloxy,di-C₁₋₆ alkyl-carbamoyloxy, C₆₋₁₄ aryl-carbamoyloxy and nicotinoyloxy,(21) a 4- to 14-membered heterocyclic group having, in addition tocarbon atoms, 1 to 4 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms, (22) a phosphono group, (23) a C₆₋₁₄ aryloxy group, (24) adi-C₁₋₆ alkoxy-phosphoryl group, (25) a C₆₋₁₄ arylthio group, (26) ahydrazino group, (27) an imino group, (28) an oxo group, (29) an ureidogroup, (30) a C₁₋₆ alkyl-ureido group, (31) a di-C₁₋₆-alkyl-ureidogroup, (32) an oxide group and (33) a group formed by binding 2 or 3groups selected from (1) to (32) listed above,

[0033] (ii) a 5- to 14-membered heterocyclic group having, in additionto carbon atoms, 1 to 4 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms which may have 1 to 5 substituent(s) selected fromSubstituent Group A described above,

[0034] (iii) an amino group which may have 1 or 2 substituent(s)selected from the following (ia) to (iiia):

[0035] (ia) a hydrogen atom,

[0036] (iia) a C₁₋₆ alkyl group, C₂₋₆ alkenyl group, C₂₋₆ alkynyl group,C₃₋₆ cycloalkyl group, C₃₋₆ cycloalkenyl group, C₆₋₁₄ aryl group orC₇₋₁₆ aralkyl group which may have 1 to 5 substituent(s) selected fromSubstituent Group A described above,

[0037] (iiia) an acyl group selected from formyl, carboxy, carbamoyl,C₁₋₆ alkyl-carbonyl, C₃₋₆ cycloalkyl-carbonyl, C₁₋₆ alkoxy-carbonyl,C₆₋₁₄ aryl-carbonyl, C₇₋₁₆ aralkyl-carbonyl, C₆₋₁₄ aryloxy-carbonyl,C₇₋₁₆ aralkyloxy-carbonyl, (5- or 6-membered heterocycle having, inaddition to carbon atoms, 1 to 3 heteroatom(s) selected from nitrogen,sulfur and oxygen atoms)-carbonyl, mono-C₁₋₆ alkyl-carbamoyl, di-C₁₋₆alkyl carbamoyl, C₆₋₁₄ aryl-carbamoyl, (5- or 6-membered heterocyclehaving, in addition to carbon atoms, 1 to 3 heteroatom(s)-selected fromnitrogen, sulfur and oxygen atoms)-carbamoyl, C₁₋₆ alkyl-thiocarbonyl,C₃₋₆ cycloalkyl-thiocarbonyl, C₁₋₆ alkoxy-thiocarbonyl, C₆₋₁₄aryl-thiocarbonyl,, C₇₋₁₆ aralkyl-thiocarbonyl, C₆₋₁₄aryloxy-thiocarbonyl, C₇₋₁₆ aralkyloxy-thiocarbonyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbonyl,thiocarbamoyl, mono-C₁₋₆ alkyl-thiocarbamoyl, di-C₁₋₆alkyl-thiocarbamoyl, C₆₋₁₄ aryl-thiocarbamoyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbamoyl,mono-C₁₋₆ alkylsulfamoyl, di-C₁₋₆ alkylsulfamoyl, C₆₋₁₄ arylsulfamoyl,C₁₋₆ alkylsulfonyl, C₆₋₁₄ arylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₄arylsulfinyl, sulfino, sulfo, C₁₋₆ alkoxysulfinyl, C₆₋₁₄aryloxysulfinyl, C₁₋₆ alkoxysulfonyl and C₆₋₁₄ aryloxysulfonyl, whichmay have 1 to 5 substituent(s) selected from Substituent Group Adescribed above;

[0038] each of R² and R³ is any of the following (i) to (iii):

[0039] (i) a hydrogen atom,

[0040] (ii) a C₁₋₆ alkyl group, C₂₋₆ alkenyl group, C₂₋₆ alkynyl group,C₃₋₆ cycloalkyl group, C₃₋₆ cycloalkenyl group, C₆₋₁₄ aryl group orC₇₋₁₆ aralkyl group which may have 1 to 5 substituent(s) selected fromSubstituent Group A described above,

[0041] (iii) an acyl group selected from formyl, carboxy, carbamoyl,C₁₋₆ alkyl-carbonyl, C₃₋₆ cycloalkyl-carbonyl, C₁₋₆ alkoxy-carbonyl,C₆₋₁₄ aryl-carbonyl, C₇₋₁₆ aralkyl-carbonyl, C₆₋₁₄ aryloxy-carbonyl,C₇₋₁₆ aralkyloxy-carbonyl, (5- or 6-membered heterocycle having, inaddition to carbon atoms, 1 to 3 heteroatom(s) selected from nitrogen,sulfur and oxygen atoms)-carbonyl, mono-C-₁₆ alkyl-carbamoyl, di-C₁₋₆alkyl-carbamoyl, C₆₋₁₄ aryl-carbamoyl, (5- or 6-membered heterocyclehaving, in addition to carbon atoms, 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms)-carbamoyl, C₁₋₆ alkyl-thiocarbonyl,C₃₋₆ cycloalkyl-thiocarbonyl, C₁₋₆ alkoxy-thiocarbonyl, C₆₋₁₄aryl-thiocarbonyl, C₇₋₁₆ aralkyl-thiocarbonyl, C₆₋₁₄aryloxy-thiocarbonyl, C₇₋₁₆ aralkyloxy-thiocarbonyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3heteroatom(s).selected from nitrogen, sulfur and oxygenatoms)-thiocarbonyl, thiocarbamoyl, mono-C₁₋₆ alkyl-thiocarbamoyl,di-C₁₋₆ alkyl-thiocarbamoyl, C₆₋₁₄ aryl-thiocarbamoyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbamoyl,mono-C₁₋₆ alkylsulfamoyl, di-C₁₋₆ alkylsulfamoyl, C₆₋₁₄ arylsulfamoyl,C₁₋₆ alkylsulfonyl, C₆₋₁₄ arylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₄arylsulfinyl, sulfino, sulfo, C₁₋₆ alkoxysulfinyl, C₆₋₁₄aryloxysulfinyl, C₁₋₆ alkoxysulfonyl and C₆₋₁₄ aryloxysulfonyl, whichmay have 1 to 5 substituent(s) selected from Substituent Group Adescribed above;

[0042] R² and R³ may be taken together with the adjacent carbon atom toform a C₃₋₈ cycloalkane or 3- to 8-membered heterocyclic ring which mayhave 1 to 3 substituent(s) selected from C₁₋₆ alkyl, C₆₋₁₄ aryl, C₇₋₁₆aralkyl, amino, mono-C₁₋₆ alkylamino, mono-C₆₋₁₄ arylamino, di-C₁₋₆alkylamino, di-C₆₋₁₄ arylamino and 4- to 10-membered aromaticheterocyclic group;

[0043] R⁴ is (i) a hydrogen atom, (ii) a cyano group, (iii) a C₁₋₆ alkylgroup, C₂₋₆ alkenyl group, C₂₋₆ alkynyl group, C₃₋₆ cycloalkyl group,C₃₋₆ cycloalkenyl group, C₆₋₁₄ aryl group or C₇₋₁₆ aralkyl group whichmay have 1 to 5 substituent(s) selected from Substituent Group Adescribed above,

[0044] (iv) an acyl group selected from formyl, carboxy, carbamoyl, C₁₋₆alkyl-carbonyl, C₃₋₆ cycloalkyl-carbonyl, C₁₋₆ alkoxy-carbonyl, C₆₋₁₄aryl-carbonyl, C₇₋₁₆ aralkyl-carbonyl, C₆₋₁₄ aryloxy-carbonyl, C₇₋₁₆aralkyloxy-carbonyl, (5- or 6-membered heterocycle having, in additionto carbon atoms, 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms)-carbonyl, mono-C₁₋₆ alkyl-carbamoyl, di-C₁₋₆alkyl-carbamoyl, C₆₋₁₄ aryl-carbamoyl, (5- or 6-membered heterocyclehaving, in addition to carbon atoms, 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms)-carbamoyl, C₁₋₆ alkyl-thiocarbonyl,C₃₋₆ cycloalkyl-thiocarbonyl, C₁₋₆ alkoxy-thiocarbonyl, C₆₋₁₄aryl-thiocarbonyl, C₇₋₁₆ aralkyl-thiocarbonyl, C₆₋₁₄aryloxy-thiocarbonyl, C₇₋₁₆ aralkyloxy-thiocarbonyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbonyl,thiocarbamoyl, mono-C₁₋₆ alkyl-thiocarbamoyl, di-C₁₋₆alkyl-thiocarbamoyl, C₆₋₁₄ aryl-thiocarbamoyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbamoyl,mono-C₁₋₆ alkylsulfamoyl, di-C₁₋₆ alkylsulfamoyl, C₆₋₁₄ arylsulfamoyl,C₁₋₆ alkylsulfonyl, C₆₋₁₄ arylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₄arylsulfinyl, sulfino, sulfo, C₁₋₆ alkoxysulfinyl, C₆₋₁₄aryloxysulfinyl, C₁₋₆ alkoxysulfonyl and C₆₋₁₄ aryloxysulfonyl, whichmay have 1 to 5 substituent(s) selected from Substituent Group Adescribed above, or,

[0045] (v) a group represented by Formula: —OR⁴′

[0046] (R⁴ is <1> a hydrogen atom,

[0047] <2> a C₁₋₆ alkyl group, C₂₋₆ alkenyl group, C₂₋₆ alkynyl group,C₃₋₆ cycloalkyl group, C₃₋₆ cycloalkenyl group, C₆₋₁₄ aryl group orC₇₋₁₆ aralkyl group which may have 1 to 5 substituent(s) selected fromSubstituent Group A described above, or,

[0048] <3> an acyl group selected from formyl, carboxy, carbamoyl, C₁₋₆alkyl-carbonyl, C₃₋₆ cycloalkyl-carbonyl, C₁₋₆ alkoxy-carbonyl, C₆₋₁₄aryl-carbonyl, C₇₋₁₆ aralkyl-carbonyl, C₆₋₁₄ aryloxy-carbonyl, C₇₋₁₆aralkyloxy-carbonyl, (5- or 6-membered heterocycle having, in additionto carbon atoms, 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms)-carbonyl, mono-C₁₋₆ alkyl-carbamoyl, di-C₁₋₆alkyl-carbamoyl, C₆₋₁₄ aryl-carbamoyl, (5- or 6-membered heterocyclehaving, in addition to carbon atoms, 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms)-carbamoyl, C₁₋₆ alkyl-thiocarbonyl,C₃₋₆ cycloalkyl-thiocarbonyl, C₁₋₆ alkoxy-thiocarbonyl, C₆₋₁₄aryl-thiocarbonyl, C₇₋₁₆ aralkyl-thiocarbonyl, C₆₋₁₄aryloxy-thiocarbonyl, C₇₋₁₆ aralkyloxy-thiocarbonyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbonyl,thiocarbamoyl, mono-C₁₋₆ alkyl-thiocarbamoyl, di-C₁₋₆alkyl-thiocarbamoyl, C₆₋₁₄ aryl-thiocarbarnoyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbamoyl,mono-C₁₋₆ alkylsulfamoyl, di-C₁₋₆ alkylsulfamoyl, C₆₋₁₄ arylsulfamoyl,C₁₋₆ alkylsulfonyl, C₆₋₁₄ arylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₄arylsulfinyl, sulfino, sulfo, C₁₋₆ alkoxysulfinyl, C₆₋₁₄aryloxysulfinyl, C₁₋₆ alkoxysulfonyl and C₆₋₁₄ aryloxysulfonyl, whichmay have 1 to 5 substituent(s) selected from Substituent Group Adescribed above);

[0049] R⁵ is any of the following (i) to (v):

[0050] (i) a hydrogen atom,

[0051] (ii) a C₁₋₆ alkyl group, C₂₋₆ alkenyl group, C₂₋₆ alkynyl group,C₃₋₆ cycloalkyl group, C₃₋₆ cycloalkenyl group, C₆₋₁₄ aryl group orC₇₋₁₆ aralkyl group which may have 1 to 5 substituent(s) selected fromSubstituent Group A described above,

[0052] (iii) an acyl group selected from formyl, carboxy, carbamoyl,C₁₋₆ alkyl-carbonyl, C₃₋₆ cycloalkyl-carbonyl, C₁₋₆ alkoxy-carbonyl,C₆₋₁₄ aryl-carbonyl, C₇₋₁₆ aralkyl-carbonyl, C₆₋₁₄ aryloxy-carbonyl,C₇₋₁₆ aralkyloxy-carbonyl, (5- or 6-membered heterocycle having, inaddition to carbon atoms, 1 to 3 heteroatom(s) selected from nitrogen,sulfur and oxygen atoms)-carbonyl, mono-C₁₋₆ alkyl-carbamoyl, di-C₁₋₆alkyl-carbamoyl, C₆₋₁₄ aryl-carbamoyl, (5- or 6-membered heterocyclehaving, in addition to carbon atoms, 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms)-carbamoyl, C₁₋₆ alkyl-thiocarbonyl,C₃₋₆ cycloalkyl-thiocarbonyl, C₁₋₆ alkoxy-thiocarbonyl, C₆₋₁₄aryl-thiocarbonyl, C₇₋₁₆ aralkyl-thiocarbonyl, C₆₋₁₄aryloxy-thiocarbonyl, C₇₋₁₆ aralkyloxy-thiocarbonyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbonyl,thiocarbamoyl, mono-C₁₋₆ alkyl-thiocarbamoyl, di-C₁₋₆alkyl-thiocarbamoyl, C₆₋₁₄ aryl-thiocarbamoyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbamoyl,mono-C₁₋₆ alkylsulfamoyl, di-C₁₋₆ alkylsulfamoyl, C₆₋₁₄ arylsulfamoyl,C₁₋₆ alkylsulfonyl, C₆₋₁₄ arylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₄arylsulfinyl, sulfino, sulfo, C₁₋₆ alkoxysulfinyl, C₆₋₁₄aryloxysulfinyl, C₁₋₆ alkoxysulfonyl and C₆₋₁₄ aryloxysulfonyl, whichmay have 1 to 5 substituent(s) selected from Substituent Group Adescribed above,

[0053] (iv) a 5- to 14-membered heterocyclic ring containing 1 to 4heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms which may contain 1 to 5 substituent(s)selected from Substituent Group A described above,

[0054] (v) a halogen atom;

[0055] each of R⁶ and R⁷ is (i) a hydrogen atom, (ii) a C₁₋₆ alkylgroup, C₂₋₆ alkenyl group, C₂₋₆ alkynyl group, C₃₋₆ cycloalkyl group,C₃₋₆ cycloalkenyl group, C₆4₁₄ aryl group or C₇₋₁₆ aralkyl group whichmay have 1 to 5 substituent(s) selected from Substituent Group Adescribed above,

[0056] R⁶ and R⁷ may be taken together with the adjacent carbon atom toform a C₃₋₈ cycloalkane or 3- to 8-membered heterocyclic ring which mayhave 1 to 3 substituent(s) selected from C₁₋₆ alkyl, C₆₋₁₄ aryl, C₇₋₁₆aralkyl, amino, mono-C₁₋₆ alkylamino, mono-C₆₋₁₄ arylamino, di-C₁₋₆alkylamino, di-C₆₋₁₄ arylamino and 4- to 10-membered aromaticheterocyclic group;

[0057] each of R⁸ and R⁹ is (i) a hydrogen atom, (ii) a C₁₋₆ alkylgroup, C₂₋₆ alkenyl group, C₂₋₆ alkynyl group, C₃₋₆ cycloalkyl group,C₃₋₆ cycloalkenyl group, C₆₋₁₄ aryl group or C₇₋₁₆ aralkyl group whichmay have 1 to 5 substituent(s) selected from Substituent Group Adescribed above;

[0058] X is (i) a bond, (ii) an oxygen atom, (iii) an optionallyoxidized sulfur atom, (iv) a C₁₋₆ alkyl group, C₂₋₆ alkenyl group, C₂₋₆alkynyl group, C₃₋₆ cycloalkyl group, C₃₋₆ cycloalkenyl group, C₆₋₁₄aryl group or C₇₋₁₆ aralkyl group which may have 1 to 5 substituent(s)selected from Substituent Group A described above,

[0059] (v) a nitrogen atom having an acyl group selected from formyl,carboxy, carbamoyl, C₁₋₆ alkyl-carbonyl, C₃₋₆ cycloalkyl-carbonyl, C₁₋₆alkoxy-carbonyl, C₆₋₁₄ aryl-carbonyl, C₇₋₁₆ aralkyl-carbonyl, C₆₋₁₄aryloxy carbonyl, C₇₋₁₆ aralkyloxy-carbonyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-carbonyl, mono-C₁₋₆alkyl-carbamoyl, di-C₁₋₆ alkyl carbamoyl, C₆₋₁₄ aryl-carbamoyl, (5- or6-membered heterocycle having, in addition to carbon atoms, 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygenatoms)-carbamoyl, C₁₋₆ alkyl-thiocarbonyl, C₃₋₆ cycloalkyl-thiocarbonyl,C₁₋₆ alkoxy-thiocarbonyl, C₆₋₁₄ aryl-thiocarbonyl, C₇₋₁₆aralkyl-thiocarbonyl, C₆₋₁₄ aryloxy-thiocarbonyl, C₇₋₁₆aralkyloxy-thiocarbonyl, (5- or 6-membered heterocycle having, inaddition to carbon atoms, 1 to 3 heteroatom(s) selected from nitrogen,sulfur and oxygen atoms)-thiocarbonyl, thiocarbamoyl, mono-C₁₋₆alkyl-thiocarbamoyl, di-C₁₋₆ alkyl-thiocarbamoyl, C₆₋₁₄aryl-thiocarbamoyl, (5- or 6-membered heterocycle having, in addition tocarbon atoms, 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms)-thiocarbamoyl, mono-C₁₋₆ alkylsulfamoyl, di-C₁₋₆alkylsulfamoyl, C₆₋₁₄ arylsulfamoyl, C₁₋₆ alkylsulfonyl, C₆₋₁₄arylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₄ arylsulfinyl, sulfino, sulfo,C₁₋₆ alkoxysulfinyl, C₆₋₁₄ aryloxysulfinyl, C₁₋₆ alkoxysulfonyl andC₆₋₁₄ aryloxysulfonyl, which may have 1 to 5 substituent(s) selectedfrom Substituent Group A described above, or,

[0060] (vi) a 5- to 14-membered heterocyclic group containing 1 to 4heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms which may contain 1 to 5 substituent(s)selected from Substituent Group A described above;

[0061] Y is <1> a methylene group which may have 1 to 5 substituent(s)selected from Substituent Group A described above or <2> a carbonylgroup;

[0062] n is 0 or 1,

[0063] [5] the compound according to the above-mentioned [2] or [3]wherein R¹ is (1) an optionally substituted aromatic hydrocarbon group,(2) an optionally substituted heterocyclic group, (3) an optionallysubstituted aliphatic cyclic hydrocarbon group or (4) a grouprepresented by Formula: —L—R^(1a) wherein L is methylene, carbonyl or anoptionally substituted nitrogen atom, R^(1a) is a hydrogen atom,optionally substituted aromatic group, optionally substituted hydroxygroup or optionally substituted amino group,

[0064] [6] the compound according to the above-mentioned [5] wherein

[0065] R¹ is any of the following (i) to (iv):

[0066] (i) a C₆₋₁₄ aryl group which may have 1 to 5 substituent(s)selected from Substituent Group A described above,

[0067] (ii) a 5- to 14-membered heterocyclic group containing 1 to 4heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms which may contain 1 to 5 substituent(s)selected from Substituent Group A described above,

[0068] (iii) a C₃₋₆ cycloalkyl group which may have 1 to 5substituent(s) selected from Substituent Group A described above,

[0069] (iv) a group represented by Formula: —L—R^(1a) wherein L is (a) amethylene, (b) a carbonyl or (c) a nitrogen atom which may besubstituted by the following (ia) to (iiia):

[0070] (ia) a hydrogen atom,

[0071] (iia) a C₁₋₆ alkyl group, C₂₋₆ alkenyl group, C₂₋₆ alkynyl group,C₃₋₆ cycloalkyl group, C₃₋₆ cycloalkenyl group, C₆₋₁₄ aryl group orC₇₋₁₆ aralkyl group which may have 1 to 5 substituent(s) selected fromSubstituent Group A described above,

[0072] (iiia) an acyl group selected from formyl, carboxy, carbamoyl,C₁₋₆ alkyl-carbonyl, C₃₋₆ cycloalkyl-carbonyl, C₁₋₆ alkoxy-carbonyl,C₆₋₁₄ aryl-carbonyl, C₇₋₁₆ aralkyl-carbonyl, C₆₋₁₄ aryloxy-carbonyl,C₇₋₁₆ aralkyloxy-carbonyl, (5- or 6-membered heterocycle having, inaddition to carbon atoms, 1 to 3 heteroatom(s) selected from nitrogen,sulfur and oxygen atoms)-carbonyl, mono-C₁₋₆ alkyl-carbamoyl, di-C₁₋₆alkyl-carbamoyl, C₆₋₁₄ aryl-carbamoyl, (5- or 6-membered heterocyclehaving, in addition to carbon atoms, 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms)-carbamoyl, C₁₋₆ alkyl-thiocarbonyl,C₃₋₆ cycloalkyl-thiocarbonyl, C₁₋₆ alkoxy-thiocarbonyl, C₆₋₁₄aryl-thiocarbonyl, C₇₋₁₆ aralkyl-thiocarbonyl, C₆₋₁₄aryloxy-thiocarbonyl, C₇₋₁₆ aralkyloxy-thiocarbonyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbonyl,thiocarbamoyl, mono-C₁₋₆ alkyl-thiocarbamoyl, di-C₁₋₆alkyl-thiocarbamoyl, C₆₋₁₄ aryl-thiocarbamoyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbamoyl,mono-C₁₋₆ alkylsulfamoyl, di-C₁₋₆ alkylsulfamoyl, C₆₋₁₄ arylsulfamoyl,C₁₋₆ alkylsulfonyl, C₆₋₁₄ arylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₄arylsulfinyl, sulfino, sulfo, C₁₋₆ alkoxysulfinyl, C₆₋₁₄aryloxysulfinyl, C₁₋₆ alkoxysulfonyl and C₆₋₁₄ aryloxysulfonyl, whichmay have 1 to 5 substituent(s) selected from Substituent Group Adescribed above,

[0073] R^(1a) is (i) a hydrogen atom,

[0074] (ii) <1> a C₆₋₁₄ aryl group or <2> a 5- to 14-membered aromaticheterocyclic group containing 1 to 4 heteroatom(s) selected from 1 or 2kind(s) of nitrogen, sulfur and oxygen atoms in addition to carbonatoms, both of which may contain 1 to 5 substituent(s) selected fromSubstituent Group A described above,

[0075] (iii) a hydroxy group which may have a C₁₋₆ alkyl group, C₂₋₆alkenyl group, C₂₋₆ alkynyl group, C₃₋₆ cycloalkyl group, C₃₋₆cycloalkenyl group, C₆₋₁₄ aryl group or C₇₋₁₆ aralkyl group which mayhave 1 to 5 substituent(s) selected from Substituent Group A describedabove,

[0076] (iv) an amino group which may be substituted by the following(ia) to (iiia):

[0077] (ia) a hydrogen atom, (iia) a C₁₋₆ alkyl group, C₂₋₆ alkenylgroup, C₂₋₆ alkynyl group, C₃₋₆ cycloalkyl group, C₃₋₆ cycloalkenylgroup, C₆₋₁₄ aryl group or C₇₋₁₆ aralkyl group which may have 1 to 5substituent(s) selected from Substituent Group A described above,

[0078] (iiia) an acyl group selected from formyl, carboxy, carbamoyl,C₁₋₆ alkyl-carbonyl, C₃₋₆ cycloalkyl-carbonyl, C₁₋₆ alkoxy-carbonyl,C₆₋₃ ₄ aryl-carbonyl, C₇₋₁₆ aralkyl-carbonyl, C₆₋₁₄ aryloxy-carbonyl,C₇₋₁₆ aralkyloxy-carbonyl, (5- or 6-membered heterocycle having, inaddition to carbon atoms, 1 to 3 heteroatom(s) selected from nitrogen,sulfur and oxygen atoms)-carbonyl, mono-C₁₋₆ alkyl-carbamoyl, di-C₁₋₆alkyl carbamoyl, C₆₋₁₄ aryl-carbamoyl, (5- or 6-membered heterocyclehaving, in addition to carbon atoms, 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms)-carbamoyl, C₁₋₆ alkyl-thiocarbonyl,C₃₋₆ cycloalkyl-thiocarbonyl, C₁₋₆ alkoxy-thiocarbonyl, C₆₋₁₄aryl-thiocarbonyl, C₇₋₁₆ aralkyl-thiocarbonyl, C₆₋₁₄aryloxy-thiocarbonyl, C₇₋₁₆ aralkyloxy-thiocarbonyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbonyl,thiocarbamoyl, mono-C₁₋₆ alkyl-thiocarbamoyl, di-C₁₋₆alkyl-thiocarbamoyl, C₆₋₁₄ aryl-thiocarbamoyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbamoyl,mono-C₁₋₆ alkylsulfamoyl, di-C₁₋₆ alkylsulfamoyl, C₆₋₁₄ arylsulfamoyl,C₁₋₆ alkylsulfonyl, C₆₋₁₄ arylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₄arylsulfinyl, sulfino, sulfo, C₁₋₆ alkoxysulfinyl, C₆₋₁₄aryloxysulfinyl, C₁₋₆ alkoxysulfonyl and C₆₋₁₄ aryloxysulfonyl.

[0079] [7] the compound according to the above-mentioned [2] wherein

[0080] R¹ is a group represented by Formula:

[0081] (wherein R^(1b) is a hydrogen atom or an optionally substitutedhydrocarbon group or optionally substituted heterocyclic group, Ring Dis an optionally substituted aromatic hydrocarbon ring or optionallysubstituted heterocyclic group, E is a bond, methylene, oxygen atom,optionally oxidized sulfur atom, optionally substituted nitrogen atom ora group represented by Formula: —CS—O—, —CO—O—, —S—CO—, —(CH₂)_(k)—CO—,—NR^(1C)—CO—(CH₂)_(m)—, —NR^(1C)—SO₂—(CH₂)_(m)—,—SO₂—NR^(1C)—(CH₂)_(m)—, —OCS—NR^(1C)—(CH₂)_(m)—,—NR^(1C)—CO—NR^(1C)—(CH₂)_(m)—, —NR^(1C)—CO—(CH₂)_(m)—NR^(1C)— whereinR^(1C) is a hydrogen atom, optionally substituted alkyl group or acylgroup, k is 0 or 1, m is an integer of 0 to 3).

[0082] [8] the compound according to the above-mentioned [7] wherein

[0083] R^(1b) is (i) a C₁₋₆ alkyl group, C₂₋₆ alkenyl group, C₂₋₆alkynyl group, C₃₋₆ cycloalkyl group, C₃₋₆ cycloalkenyl group, C₆₋₁₄aryl group or C₇₋₁₆ aralkyl group which may have 1 to 5 substituent(s)selected from Substituent Group A described above, or,

[0084] (ii) a 5- to 14-membered heterocyclic group containing 1 to 4heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms which may contain 1 to 5 substituent(s)selected from Substituent Group A described above;

[0085] Ring D is (i) a C₆₋₁₄ aryl ring which may have 1 to 5substituent(s) selected from Substituent Group A described above or (ii)a 5- to 14-membered heterocyclic ring containing 1 to 4 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms in addition to carbonatoms which may contain 1 to 5 substituent(s) selected from SubstituentGroup A described above;

[0086] E is any of the following (i) to (viii):

[0087] (i) a bond, (ii) methylene, (iii) an oxygen atom, (iv) anoptionally oxidized sulfur atom,

[0088] (v) a nitrogen atom having a C₁₋₆ alkyl group, C₂₋₆ alkenylgroup, C₂₋₆ alkynyl group, C₃₋₆ cycloalkyl group, C₃₋₆ cycloalkenylgroup, C₆₋₁₄ aryl group or C₇₋₁₆ aralkyl group which may have 1 to 5substituent(s) selected from Substituent Group A described above,

[0089] (vi) a nitrogen atom having an acyl group selected from formyl,carboxy, carbamoyl, C₁₋₆ alkyl-carbonyl, C₃₋₆ cycloalkyl-carbonyl, C₁₋₆alkoxy-carbonyl, C₆₋₁₄ aryl-carbonyl, C₇₋₁₆ aralkyl-carbonyl, C₆₋₁₄aryloxy-carbonyl, C₇₋₁₆ aralkyloxy-carbonyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-carbonyl, mono-C₁₋₆alkyl-carbamoyl, di-C₁₋₆ alkyl carbamoyl, C₆₋₁₄ aryl-carbamoyl, (5- or6-membered heterocycle having, in addition to carbon atoms, 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygenatoms)-carbamoyl, C₁₋₆ alkyl-thiocarbonyl, C₃₋₆ cycloalkyl-thiocarbonyl,C₁₋₆ alkoxy-thiocarbonyl, C₆₋₁₄ aryl-thiocarbonyl, C₇₋₁₆aralkyl-thiocarbonyl, C₆₋₁₄ aryloxy-thiocarbonyl, C₇₋₁₆aralkyloxy-thiocarbonyl, (5- or 6-membered heterocycle having, inaddition to carbon atoms, 1 to 3 heteroatom(s) selected from nitrogen,sulfur and oxygen atoms)-thiocarbonyl, thiocarbamoyl, mono-C₁₋₆alkyl-thiocarbamoyl, di-C₁₋₆ alkyl-thiocarbamoyl, C₆₋₁₄aryl-thiocarbamoyl, (5- or 6-membered heterocycle having, in addition tocarbon atoms, 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms)-thiocarbamoyl, mono-C₁₋₆ alkylsulfamoyl, di-C₁₋₆alkylsulfamoyl, C₆₋₁₄ arylsulfamoyl, C₁₋₆ alkylsulfonyl, C₆₋₁₄arylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₄ arylsulfinyl, sulfino, sulfo,C₁₋₆ alkoxysulfinyl, C₆₋₁₄ aryloxysulfinyl, C₁₋₆ alkoxysulfonyl andC₆₋₁₄ aryloxysulfonyl,

[0090] (vii) a nitrogen atom having a 5- to 14-membered heterocyclicgroup containing 1 to 4 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms in addition to carbon atoms which may contain 1 to 5substituent(s) selected from Substituent Group A described above;

[0091] (viii) —CS—O—, —CO—O—, —S—CO—, —(CH₂)_(k)—CO—,—NR^(1C)—CO—(CH₂)_(m)—, —NR^(1C)—SO₂—(CH₂)_(m)—,—SO₂—NR^(1C)—(CH₂)_(m)—, —O—CS—NR^(1C)—(CH₂)_(m)—,—NR^(1C)—CO—NR^(1C)—(CH₂)_(m)—or —NR^(1C)—CO—(CH₂)_(m)—NR^(1C)— (whereinR^(1C) is (ia) a hydrogen atom, (iia) a C₁₋₆ alkyl group which may have1 to 5 substituent(s) selected from Substituent Group A described above,or,

[0092] (iiia) an acyl group selected from formyl, carboxy, carbamoyl,C₁₋₆ alkyl-carbonyl, C₃₋₆ cycloalkyl-carbonyl, C₁₋₆ alkoxy-carbonyl,C₆₋₁₄ aryl-carbonyl, C₇₋₁₆ aralkyl-carbonyl, C₆₋₁₄ aryloxy-carbonyl,C₇₋₁₆ aralkyloxy-carbonyl, (5- or 6-membered heterocycle having, inaddition to carbon atoms, 1 to 3 heteroatom(s) selected from nitrogen,sulfur and oxygen atoms)-carbonyl, mono-C₁₋₆ alkyl-carbamoyl, di-C₁₋₆alkyl-carbamoyl, C₆₋₁₄ aryl-carbamoyl, (5- or 6-membered heterocyclehaving, in addition to carbon atoms, 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms)-carbamoyl, C₁₋₆ alkyl-thiocarbonyl,C₃₋₆ cycloalkyl-thiocarbonyl, C₁₋₆ alkoxy-thiocarbonyl, C₆₋₁₄aryl-thiocarbonyl, C₇₋₁₆ aralkyl-thiocarbonyl, C₆₋₁ ₄aryloxy-thiocarbonyl, C₇₋₁₆ aralkyloxy-thiocarbonyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbonyl,thiocarbamoyl, mono-C₁₋₆ alkyl-thiocarbamoyl, di-C₁₋₆alkyl-thiocarbamoyl, C₆₋₁₄ aryl-thiocarbamoyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbamoyl,mono-C₁₋₆ alkylsulfamoyl, di-C₁₋₆ alkylsulfamoyl, C₆₋₁ ₄ arylsulfamoyl,C₁₋₆ alkylsulfonyl, C₆₋₁₄ arylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₄arylsulfinyl, sulfino, sulfo, C₁₋₆ alkoxysulfinyl, C₆₋₁₄aryloxysulfinyl, C₁₋₆ alkoxysulfonyl and C₆₋₁₄ aryloxysulfonyl, whichmay have 1 to 5 substituent(s) selected from Substituent Group Adescribed above;

[0093] k is 0 or 1, m is an integer of 0 to 3).

[0094] [9] the compound according to the above-mentioned [7] wherein

[0095] R^(1b) is,

[0096] (1) a C₁₋₆ alkyl group [this C₁₋₆ alkyl group may have asubstituent selected from a halogen atom, cyano, hydroxy, C₁₋₆alkoxy-carbonyl, di-C₁₋₆ alkylamino, optionally halogenated C₁₋₆alkyl-carbonyl-amino, carboxy, carbamoyl, C₁₋₆ alkyl-carbamoyl, C₁₋₆alkyl-carbonyloxy, C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkyl-carbamoyl, (5- to6-membered heterocyclic ring containing 1 to 3 heteroatom(s) selectedfrom nitrogen, sulfur and oxygen atoms in addition to carbon atoms)-C₁₋₆alkyl-carbamoyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonylamino, (5- to 6-membered heterocyclic ring containing 1 to3 heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms)-C₁₋₆ alkylcarbamoyl, (5- to 6-memberedheterocyclic ring containing 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms in addition to carbon atoms)-amino,sulfamoyl-C₆₋₁₄ aryl, carboxy-C₆₋₁₄ aryl, C₁₋₆ alkoxy-carbonyl-C₆₋₁₄aryl, carbamoyl-C₆₋₁₄ aryl, C₁₋₆ alkyl-carbamoyl-C₆₋₁₄ aryl which mayhave a hydroxy and (4- to 10-membered heterocyclic ring containing 1 to3 heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms)-carbamoyl-C₆₋₁₄ aryl],

[0097] (2) a C₃₋₆ cycloalkyl group,

[0098] (3) a C₆₋₁₄ aryl group [this C₆₋₁₄ aryl group may have asubstituent selected from C₁₋₆ alkoxy, amino, carboxy, optionallyhalogenated C₁₋₆ alkyl-carbonylamino, C₁₋₆ alkoxy-carbonylamino,formylamino, ureido, C₁₋₆ alkylsulfonylamino, (C₁₋₆ alkyl)(C₁₋₆alkylsulfonyl) amino, C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkylamino, optionallyC₁₋₆ alkyl-esterified phosphono-C₁₋₆ alkylamino, mono- or di-C₁₋₆alkyl-carbamoyl and C₇₋₁₆ aralkyloxy-carbonylamino] or,

[0099] (4) a 5- to 14-membered heterocyclic group containing 1 to 4heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms [this heterocyclic group may be substituted by1 or 2 substituent(s) selected from a halogen atom, C₁₋₆ alkyl,carboxy-C₁₋₆ alkyl, C₁₋₆ alkyl-carbonyloxy-C₁₋₆ alkyl, C₁₋₆alkoxy-carbonyl, C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkyl, C₁₋₆alkyl-carbamoyl-C₁₋₆ alkyl, carbamoyl, oxo and 4- to 10-memberedheterocyclic group containing 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms in addition to carbon atoms];

[0100] Ring D is (i) a C₆₋₁₄ aryl ring or (ii) a 5- to 14-memberedheterocyclic ring containing 1 to 4 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms in addition to carbon atoms;

[0101] E is (i) a bond, (ii) methylene, (iii) O, (iv) S, (v) SO, (vi)SO₂, (vii) —NH—, (viii) —N(C₁₋₆ alkyl)-, (ix) —N(C₁₋₆ alkyl-carbonyl)-,(x) —N(C₁₋₆ alkoxy-carbonyl)-, (xi) —N(C₁₋₆ alkyl-sulfonyl)-,(xii)—CO—O—, (xiii)—S—CO—, (xiv) a group represented by Formula:—(CH2)_(k)—CO wherein k is 0 or 1, (xv) -NR^(f)—CO—(CH2)_(m1)— whereinR^(f) is a hydrogen atom or C₁₋₆ alkoxy-carbonyl or C₁₋₆ alkyl groupwhich may be substituted by a heterocyclic group containing 1 to 3heteroatom(s) selected from nitrogen, oxygen, sulfur atoms and the likein addition to carbon atoms, and m1 is an integer of 0 to 3,

[0102] (xvi) a group represented by Formula —NR⁹—SO₂—(CH₂)_(m2)— whereinR^(g) is a hydrogen atom or C₁₋₆ alkyl-sulfonyl group and m2 is 0,

[0103] (xvii) a group represented by Formula —SO₂—NR¹—(CH₂)_(m3)—wherein R^(h) is a hydrogen atom or C₁₋₆ alkyl group and m3 is 0 or 1,

[0104] (xviii) a group represented by Formula —O—CS—NR¹—(CH₂)_(m4)—wherein R^(i) is a hydrogen atom or C₁₋₆ alkyl group and m4 is 0 or 1,

[0105] (xix) a group represented by Formula —NR^(j)—CO—NR^(k—(CH)₂)_(m5)— wherein R^(j)is a hydrogen atom or C₁₋₆ alkyl group, R^(k) is ahydrogen atom or C₁₋₆ alkyl group and m5 is 0 or 1,

[0106] (xx) a group represented by Formula—NR^(L)CO—CH₂—(CH₂)_(m6)—NR^(m)— wherein R^(L) is a hydrogen atom orC₁₋₆ alkyl group, R^(m) is a hydrogen atom or C₁₋₆ alkyl group and m6 is0 or 1.

[0107] [10] the compound according to the above-mentioned [2] wherein R¹is a group represented by Formula:

[0108] wherein Hal is a halogen atom, Ring D is defined as described inthe above-mentioned [7],

[0109] [11] the compound according to the above-mentioned [2] wherein R¹is a group represented by Formula:

[0110] wherein each symbol is defined as described in theabove-mentioned [7] or a group represented by Formula:

[0111] wherein each symbol is defined as described in theabove-mentioned [7], each of R² and R³ is a hydrogen atom or optionallysubstituted hydrocarbon group, and R² and R³ may be taken together withthe adjacent carbon atom to form an optionally substituted 3- to8-membered ring, R⁴ is a hydrogen atom, cyano group, optionallysubstituted hydrocarbon group, acyl group or a group represented byFormula: —OR⁴ (wherein R⁴ is a hydrogen atom, optionally substitutedhydrocarbon group or acyl group), R⁵ is an optionally substitutedhydrocarbon group, each of R⁶ and R⁷ is an optionally substitutedhydrocarbon group, R⁶ and R⁷ may be taken together with the adjacentcarbon atom to form an optionally substituted 3- to 8-membered ring,each of R⁸ and R⁹ is a hydrogen atom, X is an oxygen atom or anoptionally oxidized sulfur atom, Y is methylene which may have 1 or 2C₁₋₆ alkyl group(s) and n is 0 or 1.

[0112] [12] the compound according to the above-mentioned [2] wherein

[0113] R¹ is,

[0114] (i) a C₆₋₁₄ aryl group which may have 1 to 3 substituent(s)selected from the following (1) to (23):

[0115] (1) a halogen atom,

[0116] (2) a nitro group,

[0117] (3) a C₁₋₆ alkyl group

[0118] [this C₁₋₆ alkyl group may have a substituent selected from ahalogen atom, cyano, carbamoyl, C₁₋₆ alkyl-carbamoyl, C₁₋₆alkyl-carbonyloxy, C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkyl-carbamoyl, (5- or6-membered heterocyclic ring containing 1 to 3 heteroatom(s) selectedfrom nitrogen, sulfur and oxygen atoms in addition to carbon atoms)-C₁₋₆alkyl-carbamoyl, C₁₋₆ alkylsulfonylamino, C₁₋₆ alkoxy-carbonyl andcarboxy],

[0119] (4) a C₃₋₆ cycloalkyl group,

[0120] (5) a C₆₋₁₄ aryl group

[0121] [this C₆₋₁₄ aryl group may have a substituent selected fromamino, carboxy, C₁₋₆ alkoxy-carbonyl, carbamoyl, mono- or di-C₁₋₆alkylcarbamoyl, formylamino, C₁₋₆ alkyl-carbonylamino which may have ahalogen atom or carboxy, C₆₋₁₄ aryl-carbonylamino, C₁₋₆alkoxy-carbonylamino, ureido, mono- or di-C₁₋₆ alkylureido, C₁₋₆alkylsulfonylamino, (C₁₋₆ alkyl) (C₁₋₆ alkylsulfonyl) amino, (C₁₋₆alkyl) (C₁₋₆ alkyl-carbonyl) amino, C₁₋₆ alkoxy-carbonyl-C₁₋₆alkylamino, C₆₋₁₄ aralkyloxy-carbonylamino, C₁₋₆alkyl-carbonylamino-C₁₋₆ alkyl-carbonylamino, C₁₋₆ alkylthio-C₁₋₆alkyl-carbonylamino, C₁₋₆ alkyl-sulfinyl-C₁₋₆ alkyl-carbonylamino, C₁₋₆alkyl-sulfonyl-C₁₋₆ alkyl-carbonylamino, C₆₋₁₄ aryloxy-carbonylamino andhydroxy-C₁₋₆ alkyl-carbamoyl],

[0122] (6) a C₁₋₆ alkoxy group which may have a halogen atom or C₁₋₆alkoxy-C₆₋₁₄ aryl,

[0123] (7) a C₆₋₁₄ aryloxy group,

[0124] (8) a C₁₋₆ alkylthio group which may have a carbamoyl,

[0125] (9) a C₁₋₆ alkylsulfinyl group which may have a carbamoyl,

[0126] (10) a C₆₋₁₄ arylthio group,

[0127] (11) a hydroxy group,

[0128] (12) a 5- to 14-membered heterocyclic group containing 1 to 4heteroatom(s) selected from nitrogen, sulfur and oxygen atoms

[0129] [this heterocyclic group may have a substituent selected fromoxo, carboxy-C₁₋₆ alkyl, C₁₋₆ alkyl-carbonyloxy-C₁₋₆ alkyl, C₁₋₆ alkyl,C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkyl, C₁₋₆ alkoxy-carbonyl, carbamoyl-C₁₋₆alkyl and C₁₋₆ alkyl-carbamoyl-C₁₋₆ alkyl],

[0130] (13) a carboxy group,

[0131] (14) a group represented by Formula: —CO-Hal (Hal is a halogenatom),

[0132] (15) a C₁₋₆ alkyl-carbonyl group,

[0133] (16) a C₁₋₆ alkyl-sulfonyl group,

[0134] (17) a C₁₋₆ alkoxy-carbonyl group,

[0135] (18) a sulfamoyl group

[0136] [this sulfamoyl group may have 1 or 2 substituent(s) selectedfrom C₁₋₆ alkyl, carbamoyl-C₁₋₆ alkyl, C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkyl,(5- to 8-membered heterocyclic ring which may have an oxo group)-C₁₋₆alkyl and C₁₋₆ alkyl-carbonylamino-C₆₋₁₄ aryl],

[0137] (19) a group represented by Formula: —NR^(a)R^(b)

[0138] [each of R^(a)and R^(b)is (i) a hydrogen atom, (ii) a C₁₋₆ alkyl,(iii) a (5- or 6-membered heterocyclic ring containing 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms)-C₁₋₆ alkyl, (iv) a C₁₋₆ alkoxy-carbonyl-C₁₋₆alkyl, (v) a di-C₁₋₆ alkylamino-methylene-sulfamoyl-C₁₋₆ alkyl, (vi) acarbamoyl-C₁₋₆ alkyl, (vii) a sulfamoyl-C₁₋₆ alkyl, (viii) a C₁₋₆alkyl-sulfonyl, (ix) a C₁₋₆ alkoxy-carbonyl, (x) a di-C₁₋₆alkoxy-carbonyl-C₂₋₆ alkenyl, (xi) a C₆₋₁₄ aryl, (xii) a 5- or6-membered heterocyclic group containing 1 to 3 heteroatom(s) selectedfrom nitrogen, sulfur and oxygen atoms in addition to carbon atoms [this5- or 6-membered heterocyclic group may have a substituent selected fromamino, C₁₋₆ alkyl-carboxamido and C₁₋₆ alkyl-sulfonylamino], (xiii) anoptionally halogenated C₁₋₆ alkyl-carbonyl, (xiv) a C₁₋₆ alkylthio-C₁₋₆alkyl-carbonyl, (xv) a C₁₋₆ alkylsulfinyl-C₁₋₆ alkyl-carbonyl, (xvi) aC₁₋₆ alkylsulfonyl-C₁₋₆ alkyl-carbonyl, (xvii) an amino-C₁₋₆alkyl-carbonyl, (xviii) an optionally halogenated C₁₋₆alkyl-carbonyl-amino-C₁₋₆ alkyl-carbonyl, (xix) a C₆₋₁₄ aryl-carbonyl,(xx) a carboxy-C₆₋₁₄ aryl-carbonyl, (xxi) an optionally C₁₋₆alkyl-esterified phosphono-C₁₋₆ alkyl-C₆₋₁₄ aryl-carbonyl, (xxii) a (5-or 6-membered heterocyclic ring containing 1 to 3 heteroatom(s) selectedfrom nitrogen, sulfur and oxygen atoms in addition to carbon atoms whichmay have a halogen atom, oxo or a C₁₋₆ alkoxy-carbonyl)-carbonyl,(xxiii) a (5- or 6-membered heterocyclic ring containing 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms)-C₁₋₆ alkyl-carbonyl, (xxiv) a C₆₋₁₄aryl-oxy-carbonyl, (xxv) a carboxy-C₁₋₆ alkyl, (xxvi) a carbamoyl,(xxvii) an optionally halogenated C₁₋₆ alkylcarbamoyl, (xxviii) a C₆₋₁₄arylcarbamoyl which may have a C₁₋₆ alkyl-carbonylamino, (xxix) a (5- or6-membered heterocyclic ring containing 1 to 3 heteroatom(s) selectedfrom nitrogen, sulfur and oxygen atoms in addition to carbonatoms)-carbamoyl, (xxx) a C₂₋₆ alkenyl-carbonyl, (xxxi) a (5- or6-membered heterocyclic ring containing 1 to 3 heteroatom(s) selectedfrom nitrogen, sulfur and oxygen atoms in addition to carbon atoms whichmay have an oxo group)-amino-C₁₋₆ alkyl-carbonyl, (xxxii) a (5- or6-membered heterocyclic ring containing 1 to 3 heteroatom(s) selectedfrom nitrogen, sulfur and oxygen atoms in addition to carbon atoms whichmay have an oxo group)(C₁₋₆ alkyl) amino-C₁₋₆ alkyl-carbonyl, (xxxiii) a(5- or 6-membered heterocyclic ring containing 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms in addition to carbonatoms which may have an oxo group)(C₁₋₆ alkylcarbonyl) amino-C₁₋₆alkyl-carbonyl, (xxxiv) a C₁₋₆ alkylthio-C₁₋₆ alkylcarbonyl (sulfur atommay be oxidized), (xxxv) an optionally halogenated C₁₋₆ alkylsulfonyl,(xxxvi) a sulfamoyl or (xxxvii) a C₁₋₆ alkylsulfamoyl],

[0139] (20) a group represented by Formula: —C(═O)NR^(c)R^(d)

[0140] [each of R^(c) and R^(d) is (i) a hydrogen atom, (ii) a C₁₋₆alkyl, (iii) a (5- or 6-membered heterocyclic ring containing 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms)-C₁₋₆ alkyl, (iv) a carboxy-C₁₋₆alkyl, (v) aC₁₋₆ alkoxy-carbonyl-C₁₋₆ alkyl, (vi) a di-C₁₋₆ alkylamino-C₁₋₆ alkyl,(vii) a carbamoyl-C₁₋₆ alkyl, (viii) a C₁₋₆ alkylcarbamoyl-C₁₋₆ alkyl,(ix) a (5- or 6-membered heterocyclic group containing 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms)-C₁₋₆ alkylcarbamoyl-C₁₋₆ alkyl, (x) a (5- or6-membered heterocyclic group containing 1 to 3 heteroatom(s) selectedfrom nitrogen, sulfur and oxygen atoms in addition to carbonatoms)-amino-C₁₋₆ alkyl, (xi) a sulfamoyl-C₆₋₁₄ aryl-C₁₋₆ alkyl, (xii) aC₆₋₁₄ aryl which may have a C₁₋₆ alkoxy, (xiii) an optionally C₁₋₆alkyl-esterified phosphono-C₁₋₆ alkyl-C₆₋₁₄ aryl, (xiv) a 4- to10-membered heterocyclic ring containing 1 to 3 heteroatom(s) selectedfrom nitrogen, sulfur and oxygen atoms in addition to carbon atoms [this4- to 10-membered heterocyclic group may have 1 to 2 substituent(s)selected from a halogen atom, C₁₋₆ alkyl and oxo], (xv) a C₆₋₁₄aryl-carbamoyl-C₁₋₆ alkyl, (xvi) a hydroxy-C₁₋₆ alkyl or (xvii) a (5- or6-membered heterocyclic ring containing 1 to 3 heteroatom(s) selectedfrom nitrogen, sulfur and oxygen atoms in addition to carbon atoms whichmay have a oxo group)-carbamoyl-C₁₋₆ alkyl],

[0141] (21) a cyano group,

[0142] (22) a mono- or di-C₁₋₆ alkylcarbamoylthio group,

[0143] (23) a mono- or di-C₁₋₆ alkylthiocarbamoyloxy group;

[0144] (ii) a 5- to 14-membered heterocyclic group containing 1 to 4heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms which may contain 1 to 3 substituent(s)selected from the following (1) to (8):

[0145] (1) a halogen atom,

[0146] (2) a C₁₋₆ alkyl group [this alkyl may have a substituentselected from carboxy, C₁₋₆ alkoxy, C₁₋₆ alkoxy-carbonyl, mono-C₁₋₆alkyl-amino, di-C₁₋₆ alkyl-amino, carbamoyl, C₁₋₆ alkyl-carbamoyl whichmay have a hydroxy, 4- to 10-membered heterocyclic group containing 1 to3 heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms which may have oxo, (4- to 10-memberedheterocyclic ring containing 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms in addition to carbonatoms)-carbamoyl, carbamoyl-C₁₋₆ alkyl-carbamoyl],

[0147] (3) a C₁₋₆ alkoxy group,

[0148] (4) a C₆₋₁₄ aryl group,

[0149] (5) a C₇₋₁₆ aralkyl group [this C₇₋₁₆ aralkyl group may have asubstituent selected from carboxy, C₁₋₆ alkoxy-carbonyl, carbamoyl, C₁₋₆alkyl-carbamoyl which may have hydroxy, (4- to 10-membered heterocyclicring containing 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms in addition to carbon atoms)-carbamoyl],

[0150] (6) a 4- to 10-membered heterocyclic group containing 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms [this 4- to 10-membered heterocyclic group mayhave a substituent selected from a C₁₋₆ alkyl, C₁₋₆ alkoxy-carbonyl,carbamoyl, oxo, 4- to 10-membered heterocyclic group containing 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms],

[0151] (7) an oxo group,

[0152] (8) an oxide group;

[0153] (iii) a C₃₋₆ cycloalkyl group; or,

[0154] (iv) a group represented by Formula: —L′—R^(1a)′ (L′ ismethylene, carbonyl or an optionally substituted nitrogen atom, R^(1a)′is (1) a hydrogen atom, (2) a C₆₋₁₄ aryl group which may have 1 to 5substituent(s) selected from a C₁₋₆ alkyl and C₁₋₆ alkoxy, (3) a hydroxygroup which may be substituted by a C₁₋₆ alkyl group, (4) a C₁₋₆alkyl-amino group which may be substituted by a 4- to 10-memberedheterocyclic ring containing 1 to 3 heteroatom(s) selected fromnitrogen, oxygen and sulfur atoms in addition to carbon atoms, (6) aC₆₋₁₄ aryl-amino group or (7) a (4- to 10-membered heterocyclic ringcontaining 1 to 3 heteroatom(s) selected from nitrogen, oxygen andsulfur atoms in addition to carbon atoms)-amino group),

[0155] each of R² and R³ is (1) a hydrogen atom, (2) a C₁₋₆ alkyl groupwhich may be substituted by <1> a halogen atom, <2> a hydroxy groupwhich may be substituted by a substituent selected from a C₁₋₆ alkyl,C₁₋₆ alkyl-carbonyl, C₁₋₆ alkylsulfonyl and C₇₋₁₆ aralkyl, <3> an aminogroup which may be substituted by 1 or 2 C₁₋₆ alkyl, C₁₋₆ alkyl-carbonyland C₆₋₁₄ aryl-carbonyl, <4> a 4- to 10-membered heterocyclic groupcontaining 1 to 3 heteroatom(s) selected from nitrogen, oxygen andsulfur atoms in addition to carbon atoms, <5> a thio group which may besubstituted by a C₁₋₆ alkyl, <6> a C₁₋₆ alkyl-sulfinyl group or <7> aC₁₋₆ alkyl-sulfonyl group, or (3) a C₁₋₆ alkoxy-carbonyl group,

[0156] R² and R³ may be taken together with the adjacent carbon atom toform a C₃₋₈ cycloalkane,

[0157] R⁴ is (i) a hydrogen atom, (ii) a cyano group, (iii) a C₁₋₆ alkylgroup [this C₁₋₆ alkyl group may have a substituent selected from (1) ahalogen atom, (2) a cyano group, (3) a C₁₋₆ alkoxy group, (4) a hydroxygroup, (5) an amino group, (6) a mono-C₁₋₆ alkylamino group, (7) adi-C₁₋₆ alkylamino group, (8) a tri-C₁₋₆ alkylammonium group, (8) a 4-to 10-membered heterocyclic group containing 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms in addition to carbonatoms which may have an oxo, (9) a C₆₋₁₄ arylthio, (10) an ureido, (11)a carboxy, (12) a carbamoyl, (13) a C₁₋₆ alkoxy-carbonyl, (14) amono-C₁₋₆ alkyl-carbamoyl, (15) a formylamino and (16) a C₁₋₆alkyl-carboxamide],

[0158] (iv) a C₂₋₆ alkenyl group or (v) a formyl group;

[0159] X is a bond, oxygen atom, optionally oxidized sulfur atom, —NH—or—N(methyl)-,

[0160] R⁵ is,

[0161] when X is a bond, then (i) a hydrogen atom, (ii) a C₁₋₆ alkylgroup or (iii) a halogen atom,

[0162] when X is an oxygen atom, then (i) a hydrogen atom, (ii) a C₁₋₆alkyl group [this C₁₋₆ alkyl group may have a substituent selected from(1) a halogen atom, (2) a hydroxy group, (3) an amino group, (4) acarboxy, (5) a carbamoyl, (6) a C₁₋₆ alkoxy-carbonyl, (7) a mono-C₁₋₆alkyl-carbamoyl, (8) a di-C₁₋₆ alkyl-carbamoyl, (9) a 4- to 10-memberedheterocyclic group containing 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms in addition to carbon atoms], (iii) aC₂₋₆ alkenyl group [this C₂₋₆ alkenyl group may have a C₆₋₁₄ aryl], (iv)a C₂₋₆ alkynyl group, (v) a C₃₋₆ cycloalkyl group, (vi) a C₇₋₁₆ aralkylgroup, (vii) a C₁₋₆ alkyl-carbonyl group, (viii) a C₆₋₁₄ aryl-carbonylgroup, (ix) a C₁₋₆ alkoxy-carbonyl group, (x) a mono- or di-C₁₋₆alkyl-thiocarbamoyl group, (xi) an optionally halogenated C₁₋₆alkyl-sulfonyl group or (xii) a 4- to 10-membered heterocyclic groupcontaining 1 to 4 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms in addition to carbon atoms [this heterocyclic group mayhave a C₆₋₁₄ aryl],

[0163] when X is an optionally oxidized sulfur, then (i) a C₁₋₆ alkylgroup or (ii) a mono- or di-C₁₋₆ alkyl-carbamoyl group,

[0164] when X is —NH—or —N(methyl)-, then (i) a hydrogen atom, (ii) aC₁₋₆ alkyl group [this C₁₋₆ alkyl group may have a C₁₋₆alkoxy-carbonyl], (iii) formyl, (iv) a C₁₋₆ alkyl-carbonyl group, (v) aC₁₋₆ alkoxy-carbonyl group, (vi) a carbamoyl group, (vii) a mono- ordi-C₁₋₆ alkyl-carbamoyl group or (viii) a C₁₋₆ alkyl-sulfonyl group,

[0165] each of R⁶ and R⁷ is a hydrogen atom or C₁₋₆ alkyl group,

[0166] R⁶ and R⁷ may be taken together with the adjacent carbon atom toform a C₃₋₈ cycloalkane,

[0167] Each of R⁸ and R⁹ is a hydrogen atom or a C₁₋₆ alkyl group,

[0168] Y is <1> a methylene group which may have 1 or 2 C₁₋₆ alkyl orhydroxy group or <2> a carbonyl group,

[0169] n is 0 or 1,

[0170] [13] the compound according to the above-mentioned [3] wherein

[0171] R¹ is,

[0172] (i) a C₆₋₁₄ aryl group which may have 1 to 3 substituent(s)selected from the following (1) to (20):

[0173] (1) a halogen atom,

[0174] (2) a nitro group,

[0175] (3) a C₁₋₆ alkyl group [this C₁₋₆ alkyl group may have asubstituent selected from a halogen atom, cyano, carbamoyl, C₁₋₆alkyl-carbamoyl, C₁₋₆ alkyl-carbonyloxy, C₁₋₆ alkoxy-carbonyl-C₁₋₆alkyl-carbamoyl, (5- or 6-membered heterocyclic ring containing 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms)-C₁₋₆ alkyl-carbamoyl, C₁₋₆ alkylsulfonylamino,C₁₋₆ alkoxy-carbonyl and carboxy],

[0176] (4) a C₃₋₆ cycloalkyl group,

[0177] (5) a C₆₋₁₄ aryl group

[0178] [this C₆C₁₄ aryl group may have a substituent selected fromamino, optionally halogenated C₁₋₆ alkyl-carbonylamino, ureido, C₁₋₆alkylsulfonylamino, (C₁₋₆ alkyl)(C₁₋₆ alkylsulfonyl) amino, C₁₋₆alkoxy-carbonyl-C₁₋₆ alkylamino],

[0179] (6) a C₁₋₆ alkoxy group which may have a halogen atom or C₁₋₆alkoxy-C₆₋₁₄ aryl,

[0180] (7) a C₆₋₁₄ aryloxy group,

[0181] (8) a C₁₋₆ alkylthio group,

[0182] (9) a C₁₋₆ alkylsulfinyl group,

[0183] (10) a C₆₋₁₄ arylthio group,

[0184] (11) a hydroxy group,

[0185] (12) a 5- to 14-membered heterocyclic group containing 1 to 4heteroatom(s) selected from nitrogen, sulfur and oxygen atoms [thisheterocyclic group may have a substituent selected from oxo,carboxy-C₁₋₆ alkyl, C₁₋₆ alkyl-carbonyloxy-C₁₋₆ alkyl, C₁₋₆alkoxy-carbonyl-C₁₋₆ alkyl, C₁₋₆ alkyl-carbamoyl-C₁₋₆ alkyl],

[0186] (13) a carboxy group,

[0187] (14) a group represented by Formula: —CO-Hal (Hal is a halogenatom),

[0188] (15) a C₁₋₆ alkyl-carbonyl group,

[0189] (16) a C₁₋₆ alkyl-sulfonyl group,

[0190] (17) a C₁₋₆ alkoxy-carbonyl group,

[0191] (18) a sulfamoyl group [this sulfamoyl group may have asubstituent selected from a C₁₋₆ alkyl, carbamoyl-C₁₋₆ alkyl, (5- or6-membered heterocyclic ring containing 1 to 3 heteroatom(s) selectedfrom nitrogen, sulfur and oxygen atoms in addition to carbon atoms)-C₁₋₆alkyl],

[0192] (19) a group represented by Formula: —NR^(a)R^(b) [each of R^(a)and R^(b)is (i) a hydrogen atom, (ii) a C₁₋₆ alkyl, (iii) a (5- or6-membered heterocyclic ring containing 1 to 3 heteroatom(s) selectedfrom nitrogen, sulfur and oxygen atoms in addition to carbon atoms)-C₁₋₆alkyl, (iv) a C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkyl, (v) a di-C₁₋₆alkylamino-methylene-sulfamoyl-C₁₋₆ alkyl, (vi) a carbamoyl-C₁₋₆ alkyl,(vii) a sulfamoyl-C₁₋₆ alkyl, (viii) a C₁₋₆ alkyl-sulfonyl, (ix) a C₁₋₆alkoxy-carbonyl, (x) a di-C₁₋₆ alkoxy-carbonyl-C₂₋₆ alkenyl, (xi) aC₆₋₁₄ aryl, (xii) a 5- or 6-membered heterocyclic group containing 1 to3 heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms [this 5- or 6-membered heterocyclic group mayhave a substituent selected from amino, C₁₋₆ alkyl-carboxamido and C₁₋₆alkyl-sulfonylamino], (xiii) an optionally halogenated C₁₋₆alkyl-carbonyl, (xiv) a C₁₋₆ alkylthio-C₁₋₆ alkyl-carbonyl, (xv) a C₁₋₆alkylsulfinyl-C₁₋₆ alkyl-carbonyl, (xvi) a C₁₋₆ alkylsulfonyl-C₁₋₆alkyl-carbonyl, (xvii) an amino-C₁₋₆ alkyl-carbonyl, (xviii) anoptionally halogenated C₁₋₆ alkyl-carbonyl-amino-C₁₋₆ alkyl-carbonyl,(xix) a C₆₋₁₄ aryl-carbonyl, (xx) a carboxy-C₆₋₁₄ aryl-carbonyl, (xxi)an optionally C₁₋₆ alkyl-esterified phosphono-C₁₋₆ alkyl-C₆₋₁₄aryl-carbonyl, (xxii) a (5- or 6-membered heterocyclic ring containing 1to 3 heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms)-carbonyl, (xxiii) a (5- or 6-memberedheterocyclic ring containing 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms in addition to carbon atoms which mayhave a C₁₋₆ alkoxy-carbonyl)-C₁₋₆ alkyl-carbonyl, (xxiv) a C₆₋₁₄aryl-oxy-carbonyl, (xxv) a carboxy-C₁₋₆ alkyl or (xxvi) a -carbamoyl],

[0193] (20) a group represented by Formula: —C(═O)NR^(c)R^(d) [each ofR^(c) and R^(d) is (i) a hydrogen atom, (ii) a C₁₋₆ alkyl, (iii) a (5-or 6-membered heterocyclic ring containing 1 to 3 heteroatom(s) selectedfrom nitrogen, sulfur and oxygen atoms in addition to carbon atoms)-C₁₋₆alkyl, (iv) a carboxy-C₁₋₆ alkyl, (v) a C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkyl,(vi) a di-C₁₋₆ alkylamino-C₁₋₆ alkyl, (vii) a carbamoyl-C₁₋₆ alkyl,(viii) a C₁₋₆ alkylcarbamoyl-C₁₋₆ alkyl, (ix) a (5- or 6-memberedheterocyclic group containing 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms-C₁₋₆ alkyl carbamoyl)-C₁₋₆ alkyl, (x)a (5- or 6-membered heterocyclic group containing 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms in addition to carbonatoms)-amino-C₁₋₆ alkyl, (xi) a sulfamoyl-C₆₋₁₄ aryl-C₁₋₆ alkyl, (xii) aC₆₋₁₄ aryl which may have a C₁₋₆ alkoxy, (xiii) a C₁₋₆ alkyl-C₆₋₁₄ arylwhich have an optionally C₁₋₆ alkyl-esterified phosphono group, (xiv) a4- to 10-membered heterocyclic ring containing 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms in addition to carbonatoms [this heterocyclic group may have 1 to 2 substituent(s) selectedfrom a halogen atom, C₁₋₆ alkyl and oxo] or (xv) a C₆₋₁₄aryl-carbamoyl-C₁₋₆ alkyl;

[0194] (ii) a 5- to 14-membered heterocyclic group containing 1 to 4heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms which may contain 1 to 3 substituent(s)selected from the following (1) to (8):

[0195] (1) a halogen atom,

[0196] (2) a C₁₋₆ alkyl group [this alkyl may have a substituentselected from carboxy, C₁₋₆ alkoxy, C₁₋₆ alkoxy-carbonyl, mono-C₁₋₆alkyl-amino, di-C₁₋₆ alkyl-amino, carbamoyl, C₁₋₆ alkyl-carbamoyl whichmay have a hydroxy, 4- to 10-membered heterocyclic group containing 1 to3 heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms which may have oxo, (4- to 10-memberedheterocyclic ring containing 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms in addition to carbonatoms)-carbamoyl, carbamoyl-C₁₋₆ alkyl-carbamoyl],

[0197] (3) a C₁₋₆ alkoxy group,

[0198] (4) a C₆₋₁₄ aryl group,

[0199] (5) a C₇₋₁₆ aralkyl group [this C₇₋₁₆ aralkyl group may have asubstituent selected from carboxy, C₁₋₆ alkoxy-carbonyl, carbamoyl, C₁₋₆alkyl-carbamoyl which may have a hydroxy, (4- to 10-memberedheterocyclic ring containing 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms in addition to carbonatoms)-carbamoyl],

[0200] (6) a 4- to 10-membered heterocyclic group containing 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms [this 4- to 10-membered heterocyclic group mayhave a substituent selected from a C₁₋₆ alkyl, C₁₋₆ alkoxy-carbonyl,carbamoyl, oxo, 4- to 10-membered heterocyclic group containing 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms],

[0201] (7) an oxo group,

[0202] (8) an oxide group;

[0203] (iii) a C₃₋₆ cycloalkyl group; or,

[0204] (iv) a group represented by Formula: —L′—R^(1a)′ (L′ ismethylene, carbonyl or —NH—, R^(1a)′ is (1) a hydrogen atom, (2) a C₆₋₁₄aryl group which may have 1 to 5 substituent(s) selected from a C₁₋₆alkyl and C₁₋₆ alkoxy, (3) a hydroxy group which may be substituted by aC₁₋₆ alkyl group, (4) a C₁₋₆ alkyl-amino group which may be substitutedby a 4- to 10-membered heterocyclic ring containing 1 to 3 heteroatom(s)selected from nitrogen, oxygen and sulfur atoms in addition to carbonatoms, (6) a C₆₋₁₄ aryl-amino group or (7) a (4- to 10-memberedheterocyclic ring containing 1 to 3 heteroatom(s) selected fromnitrogen, oxygen and sulfur atoms in addition to carbon atoms)-aminogroup),

[0205] each of R² and R³ is (1) a hydrogen atom, (2) an optionallyhalogenated C₁₋₆ alkyl group or (3) a C₁₋₆ alkoxy-carbonyl group,

[0206] R² and R may be taken together with the adjacent carbon atom toform a C₃₋₈ cycloalkane,

[0207] R⁴ is (i) a hydrogen atom, (ii) a C₁₋₆ alkyl group [this C₁₋₆alkyl group may have a substituent selected from (1) a halogen atom, (2)a cyano group, (3) a C₁₋₆ alkoxy group, (4) a hydroxy group, (5) anamino group, (6) a mono-C₁₋₆ alkylamino group, (7) a di-C₁₋₆ alkylaminogroup, (8) a tri-C₁₋₆ alkylammonium group, (9) a 4- to 10-memberedheterocyclic group containing 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms in addition to carbon atoms which mayhave an oxo, (10) a C₆₋₁₄ arylthio, (11) an ureido, (12) a carboxy, (13)a carbamoyl, (14) a C₁₋₆ alkoxy-carbonyl, (15) a mono-C₁₋₆alkyl-carbamoyl, (16) a formylamino, (17) a C₁₋₆ alkyl-carboxamido] or(iii) a C₂₋₆ alkenyl group;

[0208] X is a bond,-oxygen atom, sulfur atom, —NH—or —N(methyl)-,

[0209] R⁵ is,

[0210] when X is a bond, then (i) a hydrogen atom, (ii) a C₁₋₆ alkylgroup or (iii) a halogen atom,

[0211] when X is an oxygen atom, then (i) a hydrogen atom, (ii) a C₁₋₆alkyl group [this C₁₋₆ alkyl group may have a substituent selected from(1) a halogen atom, (2) a hydroxy group, (3) an amino group, (4) acarboxy, (5) a carbamoyl, (6) a C₁₋₆ alkoxy-carbonyl, (7) a mono-C₁₋₆alkyl-carbamoyl, (8) a di-C₁₋₆ alkyl-carbamoyl, (9) a 4- to 10-memberedheterocyclic group containing 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms in addition to carbon atoms which mayhave an oxo], (iii) a C₂₋₆ alkenyl group [this C₂₋₆ alkenyl group mayhave a C₆₋₁₄ aryl], (iv) a C₂₋₆ alkynyl group, (v) a C₃₋₆ cycloalkylgroup, (vi) a C₇₋₁₆ aralkyl group, (vii) a C₁₋₆ alkyl-carbonyl group,(viii) a C₆₋₁₄ aryl-carbonyl group, (ix) a C₁₋₆ alkoxy-carbonyl group,(x) a mono- or di-C₁₋₆ alkyl-thiocarbamoyl group, (xi) an optionallyhalogenated C₁₋₆ alkyl-sulfonyl group or (xii) a 4- to 10-memberedheterocyclic group containing 1 to 4 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms in addition to carbon atoms [thisheterocyclic group may have a C₆₋₁₄ aryl],

[0212] when X is a sulfur, then (i) a C₁₋₆ alkyl group or (ii) a mono-or di-C₁₋₆ alkyl-carbamoyl group,

[0213] when X is —NH—or —N(methyl)-, then (i) a hydrogen atom, (ii) aC₁₋₆ alkyl group [this C₁₋₆ alkyl group may have a C₁₋₆alkoxy-carbonyl], (iii) formyl, (iv) a C₁₋₆ alkyl-carbonyl group, (v) aC₁₋₆ alkoxy-carbonyl group, (vi) a carbamoyl group, (vii) a mono- ordi-C₁₋₆ alkyl-carbamoyl group or (viii) a C₁₋₆ alkyl-sulfonyl group,

[0214] each of R⁶ and R⁷ is a hydrogen atom or C₁₋₆ alkyl group,

[0215] R⁶ and R⁷ may be taken together with the adjacent carbon atom toform a C₃₋₈ cycloalkane,

[0216] each of R⁸ and R⁹ is a hydrogen atom or a C₁₋₆ alkyl group,

[0217] Y is a methylene group which may have a hydroxy group or carbonylgroup,

[0218] n is 0 or 1.

[0219] [14] the compound according to the above-mentioned [2] wherein

[0220] each of R² and R³ is a C₁₋₆ alkyl group,

[0221] [15] the compound according to the above-mentioned [2] wherein

[0222] R⁴ is a hydrogen atom,

[0223] [16] the compound according to the above-mentioned [2] wherein

[0224] each of R⁶ and R⁷ is a C₁₋₆ alkyl group,

[0225] [17] the compound according to the above-mentioned [2] wherein

[0226] each of R⁸ and R⁹ is a hydrogen atom,

[0227] [18] the compound according to the above-mentioned [2] wherein

[0228] n is 0,

[0229] [19] (i)2-(Methylsulfinyl)—N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]acetamide,(ii)N-(methylsulfonyl)—N-[3-(3,4,8,9-tetrahydro-6-methoxy3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]methanesulfonamide,(iii)N-[2-(4-pyridinyl)ethyl]-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide,(iv)N-(2-amino-2-oxoethyl)-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide,(v)N-methyl-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide,(vi)N-ethyl-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide,(vii)N-[3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-3-yl]acetamide,(viii)N-(2-amino-1,1-dimethyl-2-oxoethyl)-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide,(ix)3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)—N-methylbenzamide,(x)N-(2-amino-2-oxoethyl)-3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide,(xi) N-(2-amino-1,1-dimethyl-2-oxoethyl)-3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide,(xii)N-[3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]methanesulfonamide,(xiii)N-(hydroxymethyl)-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamideor its salts,

[0230] [20] a prodrug of a compound according to the above-mentioned[2],

[0231] [21] a process for producing a compound having a partialstructure represented by Formula:

[0232] wherein R¹ is defined as described in the above mentioned [2], ora salt thereof, comprising:

[0233] (1) reacting a compound having a partial structure represented byFormula:

[0234] wherein R¹⁰ is an optionally substituted vinyl group or allylgroup, or a salt thereof with a compound represented by Formula: R¹—CNor Formula: R¹—CONH₂ wherein R¹ is defined as described above or a saltthereof, or,

[0235] (2) reacting a compound having a partial structure represented byFormula:

[0236] wherein R¹¹ is an optionally substituted methyl group, Z is anoptionally substituted hydroxy group or halogen atom or a salt thereofwith a compound represented by Formula: R¹—CN wherein R¹ is defined asdescribed above or a salt thereof,

[0237] [22] a process for producing a compound according to theabove-mentioned [2] comprising:

[0238] reacting a compound represented by Formula:

[0239] wherein each symbol is defined as described in theabove-mentioned [2] or a salt thereof with a compound represented byFormula: R¹—CN or Formula: R¹—CONH₂ wherein R¹ is defined as describedin the above-mentioned [2] or a salt thereof, or,

[0240] reacting a compound represented by Formula:

[0241] wherein Z is an optionally substituted hydroxy group or halogenatom, and other symbols are defined as described in the above-mentioned[2] or a salt thereof with a compound represented by Formula: R¹—CNwherein R¹ is defined as described in the above-mentioned [2] or a saltthereof,

[0242] [23] a phosphodiesterase IV inhibitor comprising a compoundhaving a partial structure represented by Formula:

[0243] wherein - - - is a single bond or double bond or a salt thereof,

[0244] [24] a pharmaceutical composition comprising a compound accordingto the above-mentioned [1] or a salt thereof,

[0245] [25] a pharmaceutical composition comprising a compound accordingto the above-mentioned [2] or a salt or prodrug thereof,

[0246] [26] the pharmaceutical composition according to theabove-mentioned [24] or [25] which is a phosphodiesterase IV inhibitor,

[0247] [27] the pharmaceutical composition according to theabove-mentioned [23] to [26] which is a prophylactic or therapeuticagent against inflammatory diseases,

[0248] [28] the pharmaceutical composition according to theabove-mentioned [23] to [26] which is a prophylactic or therapeuticagent against asthma, chronic obstructive pulmonary disease (COPD),rheumatoid arthritis, autoimmune disease or diabetes,

[0249] [29] a pharmaceutical comprising (1) a compound having a partialstructure represented by Formula:

[0250] wherein - - - is a single bond or double bond or a salt thereofin combination with (2) a drug selected from antiasthma agents,antiallergic agents, anticholinergic agents, antiinflammatory agents,antibacterial agents, antifungal agents and antidiabetic agents,

[0251] [30] a pharmaceutical comprising (1) a compound according to theabove-mentioned [1] or a salt thereof in combination with (2) a drugselected from antiasthma agents, antiallergic agents, anticholinergicagents, antiinflammatory agents, antibacterial agents, antifungal agentsand antidiabetic agents,

[0252] [31] a pharmaceutical comprising (1) a compound according to theabove-mentioned [2] or a salt or prodrug thereof in combination with (2)a drug selected from antiasthma agents, antiallergic agents,anticholinergic agents, antiinflammatory agents, antibacterial agents,antifungal agents and antidiabetic agents,

[0253] [32] the pharmaceutical according to the above-mentioned [29] to[31] which is a prophylactic or therapeutic agent against inflammatorydiseases,

[0254] [33] the pharmaceutical according to the above-mentioned [29] to[31] which is a prophylactic or therapeutic agent against asthma,chronic obstructive pulmonary disease (COPD), rheumatoid arthritis,autoimmune disease or diabetes,

[0255] [34] Escherichia coli BL21/pPDE4D3 (FERM BP-7075),

[0256] [35] a method for inhibiting a phosphodiesterase IV comprisingadministering an effective amount of a compound having a partialstructure represented by Formula:

[0257] wherein - - - is a single bond or double bond or a salt thereofto a mammal,

[0258] [36] a method for preventing or treating inflammatory diseasescomprising administering an effective amount of a compound having apartial structure represented by Formula:

[0259] wherein - - - is a single bond or double bond or a salt thereofto a mammal,

[0260] [37] a method for preventing or treating asthma, chronicobstructive pulmonary disease (COPD), rheumatoid arthritis, autoimmunedisease or diabetes comprising administering an effective amount of acompound having a partial structure represented by Formula:

[0261] wherein - - - is a single bond or double bond or a salt thereofto a mammal,

[0262] [38] a method for inhibiting a phosphodiesterase IV comprisingadministering an effective amount of the compound according to theabove-mentioned [1] or a salt thereof to a mammal,

[0263] [39] a method for preventing or treating inflammatory diseasescomprising administering an effective amount of the compound accordingto the above-mentioned [1] or a salt thereof to a mammal,

[0264] [40] a method for preventing or treating asthma, chronicobstructive pulmonary disease (COPD), rheumatoid arthritis, autoimmunedisease or diabetes comprising administering an effective amount of thecompound according to the above-mentioned [1] or a salt thereof to amammal,

[0265] [41] a method for inhibiting a phosphodiesterase IV comprisingadministering an effective amount of the compound according to theabove-mentioned [2] or a salt or prodrug thereof to a mammal,

[0266] [42] a method for preventing or treating inflammatory diseasescomprising administering an effective amount of the compound accordingto the above-mentioned [2] or a salt or prodrug thereof to a mammal,

[0267] [43] a method for preventing or treating asthma, chronicobstructive pulmonary disease (COPD), rheumatoid arthritis, autoimmunedisease or diabetes comprising administering an effective amount of thecompound according to the above-mentioned [2] or a salt or prodrugthereof to a mammal,

[0268] [44] a method for preventing or treating inflammatory diseasescomprising administering (1) an effective amount of a compound having apartial structure represented by Formula:

[0269] wherein - - - is a single bond or double bond or a salt thereofin combination with (2) an effective amount of a drug selected fromantiasthma agents, antiallergic agents, anticholinergic agents,antiinflammatory agents, antibacterial agents, antifungal agents andantidiabetic agents to a mammal,

[0270] [45] a method for preventing or treating asthma, chronicobstructive pulmonary disease (COPD), rheumatoid arthritis, autoimmunedisease or diabetes comprising administering (1) an effective amount ofa compound having a partial structure represented by Formula:

[0271] wherein - - - is a single bond or double bond or a salt thereofin combination with (2) an effective amount of a drug selected fromantiasthma agents, antiallergic agents, anticholinergic agents,antiinflammatory agents, antibacterial agents, antifungal agents andantidiabetic agents to a mammal,

[0272] [46]-a method for preventing or treating inflammatory diseasescomprising administering (1) an effective amount of the compoundaccording to the above-mentioned [1] or a salt thereof in combinationwith (2) an effective amount of a drug selected from antiasthma agents,antiallergic agents, anticholinergic agents, antiinflammatory agents,antibacterial agents, antifungal agents and antidiabetic agents to amammal,

[0273] [47] a method for preventing or treating asthma, chronicobstructive pulmonary disease (COPD), rheumatoid arthritis, autoimmunedisease or diabetes comprising administering (1) an effective amount ofthe compound according to the above-mentioned [1] or a salt thereof incombination with (2) an effective amount of a drug selected fromantiasthma agents, antiallergic agents, anticholinergic agents,antiinflammatory agents, antibacterial agents, antifungal agents andantidiabetic agents to a mammal,

[0274] [48] a method for preventing or treating inflammatory diseasescomprising administering (1) an effective amount of the compoundaccording to the above-mentioned [2] or a salt or prodrug thereof incombination with (2) an effective amount of a drug selected fromantiasthma agents, antiallergic agents, anticholinergic agents,antiinflammatory agents, antibacterial agents, antifungal agents andantidiabetic agents to a mammal,

[0275] [49] a method for preventing or treating asthma, chronicobstructive pulmonary disease (COPD), rheumatoid arthritis, autoimmunedisease or diabetes comprising administering (1) an effective amount ofthe compound according to the above-mentioned [2] or a salt or prodrugthereof in combination with (2) an effective amount of a drug selectedfrom antiasthma agents, antiallergic agents, anticholinergic agents,antiinflammatory agents, antibacterial agents, antifungal agents andantidiabetic agents to a mammal,

[0276] [50] a use of a compound having a partial structure representedby Formula:

[0277] wherein - - - is a single bond or double bond or a salt thereoffor producing a phosphodiesterase IV inhibitor,

[0278] [51] a use of a compound having a partial structure representedby Formula:

[0279] wherein - - - is a single bond or double bond or a salt thereoffor producing a prophylactic or therapeutic agent against inflammatorydiseases,

[0280] [52] a use of a compound having a partial structure representedby Formula:

[0281] wherein - - - is a single bond or double bond or a salt thereoffor producing a prophylactic or therapeutic agent against asthma,chronic obstructive pulmonary disease (COPD), rheumatoid arthritis,autoimmune disease or diabetes,

[0282] [53] a use of the compound according to the above-mentioned [1]or a salt thereof for producing a phosphodiesterase IV inhibitor,

[0283] [54] a use of the compound according to the above-mentioned [1]or a salt thereof for producing a prophylactic or therapeutic agentagainst inflammatory diseases,

[0284] [55] a use of the compound according to the above-mentioned [1]or a salt thereof for producing a prophylactic or therapeutic agentagainst asthma, chronic obstructive pulmonary disease (COPD), rheumatoidarthritis, autoimmune disease or diabetes,

[0285] [56] a use of the compound according to the above-mentioned [2]or a salt or prodrug thereof for producing a phosphodiesterase IVinhibitor,

[0286] [57] a use of the compound according to the above-mentioned [2]or a salt or prodrug thereof for producing a prophylactic or therapeuticagent against inflammatory diseases,

[0287] [58] a use of the compound according to the above-mentioned [2]or a salt or prodrug thereof for producing a prophylactic or therapeuticagent against asthma, chronic obstructive pulmonary disease (COPD),rheumatoid arthritis, autoimmune disease or diabetes,

[0288] [59] a compound represented by Formula:

[0289] wherein each of R^(2a) and R^(3a) is an optionally substitutedaliphatic hydrocarbon group or acyl group,

[0290] R^(4a) is a hydrogen atom, optionally substituted hydrocarbongroup, acyl group or optionally substituted hydroxy group,

[0291] R^(5a) is an optionally substituted hydrocarbon group, acylgroup, optionally substituted heterocyclic group or halogen atom,

[0292] Each of R^(6a), R^(7a), R^(8a) and R^(9a) is a hydrogen atom oroptionally substituted hydrocarbon group,

[0293] X^(a) is a bond, oxygen atom, optionally oxidized sulfur atom oroptionally substituted nitrogen atom, or by Formula:

[0294] wherein each of R^(2a) and R^(3a) is an optionally substitutedaliphatic hydrocarbon group or acyl group,

[0295] R^(4a) is a hydrogen atom, optionally substituted hydrocarbongroup, acyl group or optionally substituted hydroxy group,

[0296] R^(5a) is an optionally substituted hydrocarbon group, acylgroup, optionally substituted heterocyclic group or halogen atom,

[0297] Each of R^(6a), R^(7a), R^(8a) and R^(9a) is a hydrogen atom oroptionally substituted hydrocarbon group,

[0298] X^(a) is a bond, oxygen atom, optionally oxidized sulfur atom oroptionally substituted nitrogen atom,

[0299] Z is an optionally substituted hydroxy group or halogen atom, ora salt thereof,

[0300] [60] the compound according to the above-mentioned [59] wherein:

[0301] each of R^(2a) and R^(2b) is any of the following (i) to (ii):

[0302] (i) a C₁₋₆ alkyl group or C₃₋₆ cycloalkyl group which may have 1to 5 substituent(s) selected from the group (hereinafter referred to asSubstituent Group B) consisting of (1) a halogen atom, (2) a C₁₋₃alkylenedioxy group, (3) a nitro group, (4) an optionally halogenatedC₁₋₆ alkyl group, (5) a C₃₋₆ cycloalkyl group, (6) a C₆₋₁₄ aryl group,(7) an optionally halogenated C₁₋₆ alkoxy group, (8) an optionallyhalogenated C₁₋₆ alkylthio group, (9) a hydroxy group, (10) an aminogroup, (11) a mono-C₁₋₆ alkylamino group, (12) a mono-C₆₋₁₄ arylaminogroup, (13) a di-C₁₋₆ alkylamino group, (14) a di-C₆₋₁₄ arylamino group,(15) an acyl group selected from formyl, carboxy, carbamoyl, C₁₋₆alkyl-carbonyl, C₃₋₆ cycloalkyl-carbonyl, C₁₋₆ alkoxy-carbonyl, C₆₋₁₄aryl-carbonyl, C₇₋₁₆ aralkyl-carbonyl, C₆₋₁₄ aryloxy-carbonyl, C₇₋₁₆aralkyloxy-carbonyl, (5- or 6-membered heterocycle having, in additionto carbon atoms, 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms)-carbonyl, mono-C₁₋₆ alkyl-carbamoyl, di-C₁₋₆ alkylcarbamoyl, C₆₋₁₄ aryl-carbamoyl, a (5- or 6-membered heterocycle having,in addition to carbon atoms, 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms)-carbamoyl, C₁₋₆ alkyl-thiocarbonyl,C₃₋₆ cycloalkyl-thiocarbonyl, C₁₋₆ alkoxy-thiocarbonyl, C₆₋₁₄aryl-thiocarbonyl, C₇₋₁₆ aralkyl-thiocarbonyl, C₆₋₁₄aryloxy-thiocarbonyl, C₇₋₁₆ aralkyloxy-thiocarbonyl, a (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbonyl,thiocarbamoyl, mono-C₁₋₆ alkyl-thiocarbamoyl, di-C₁₋₆alkyl-thiocarbamoyl, C₆₋₁₄ aryl-thiocarbamoyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbamoyl,mono-C₁₋₆ alkylsulfamoyl, di-C₁₋₆ alkylsulfamoyl, C₆₋₁₄ arylsulfamoyl,C₁₋₆ alkylsulfonyl, C₆₋₁₄ arylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₄arylsulfinyl, sulfino, sulfo, C₁₋₆ alkoxysulfinyl, C₆₋₁₄aryloxysulfinyl, C₁₋₆ alkoxysulfonyl and C₆₋₁₄ aryloxysulfonyl, (16) anacylamino group selected from formylamino, C₁₋₆ alkyl-carboxamido, C₆₋₁₄aryl-carboxamido, C₁₋₆ alkoxy-carboxamido, C₁₋₆ alkylsulfonylamino andC₆₋₁₄ arylsulfonylamino, (17) an acyloxy group selected from C₁₋₆alkyl-carbonyloxy, C₆₋₁₄ aryl-carbonyloxy, C₁₋₆ alkoxy-carbonyloxy,mono-C₁₋₆ alkyl-carbamoyloxy, di-C₁₋₆ alkyl-carbamoyloxy, C₆₋₁₄aryl-carbamoyloxy and nicotinoyloxy, (18) a 4- to 14-memberedheterocyclic group having, in addition to carbon atoms, 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygen atoms, (19) aphosphono group, (20) a C₆₋₁₄ aryloxy group, (21) a di-C₁₋₆alkoxy-phosphoryl group, (22) a C₆₋₁₄ arylthio group, (23) a hydrazinogroup, (24) an imino group, (25) an oxo group, (26) an ureido group,(27) a C₁₋₆ alkyl-ureido group, (28) a di-C₁₋₆-alkyl-ureido group, (29)an oxide group and (30) a group formed by binding 2 or 3 groups selectedfrom (1) to (29) listed above,

[0303] (ii) an acyl group selected from formyl, carboxy, carbamoyl, C₁₋₆alkyl-carbonyl, C₃₋₆ cycloalkyl-carbonyl, C₁₋₆ alkoxy-carbonyl, C₆₋₁₄aryl-carbonyl, C₇₋₁₆ aralkyl-carbonyl, C₆₋₁₄ aryloxy-carbonyl, C₇₋₁₆aralkyloxy-carbonyl, (5- or 6-membered heterocycle having, in additionto carbon atoms, 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms)-carbonyl, mono-C₁₋₆ alkyl-carbamoyl, di-C₁₋₆alkyl-carbamoyl, C₆₋₁₄ aryl-carbamoyl, (5- or 6-membered heterocyclehaving, in addition to carbon atoms, 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms)-carbamoyl, C₁₋₆ alkylthiocarbonyl,C₃₋₆ cycloalkyl-thiocarbonyl, C₁₋₆ alkoxy-thiocarbonyl, C₆₋₁₄aryl-thiocarbonyl, C₇₋₁₆ aralkyl-thiocarbonyl, C₆₋₁₄aryloxy-thiocarbonyl, C₇₋₁₆ aralkyloxy-thiocarbonyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbonyl,thiocarbamoyl, mono-C₁₋₆ alkyl-thiocarbamoyl, di-C₁₋₆alkyl-thiocarbamoyl, C₆₋₁₄ aryl-thiocarbamoyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbamoyl,mono-C₁₋₆ alkylsulfamoyl, di-C₁₋₆ alkylsulfamoyl, C₆₋₁₄ arylsulfamoyl,C₁₋₆ alkylsulfonyl, C₆₋₁₄ arylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₄arylsulfinyl, sulfino, sulfo, C₁₋₆ alkoxysulfinyl, C₆₋₁₄aryloxysulfinyl, C₁₋₆ alkoxysulfonyl and C₆₋₁₄ aryloxysulfonyl, whichmay have 1 to 5 substituent(s) selected from Substituent Group Bdescribed above;

[0304] R^(4a) is (i) a hydrogen atom,

[0305] (ii) a C₁₋₆ alkyl group, C₃₋₆ cycloalkyl group, C₆₋₁₄ aryl groupor C₇₋₁₆ aralkyl group which may have 1 to 5 substituent(s) selectedfrom Substituent Group B described above,

[0306] (iii) an acyl group selected from formyl, carboxy, carbamoyl,C₁₋₆ alkyl-carbonyl, C₃₋₆ cycloalkyl-carbonyl, C₁₋₆ alkoxy-carbonyl,C₆₋₁₄ aryl-carbonyl, C₇₋₁₆ aralkyl-carbonyl, C₆₋₁₄ aryloxy carbonyl,C₇₋₁₆ aralkyloxy-carbonyl, (5- or 6-membered heterocycle having, inaddition to carbon atoms, 1 to 3 heteroatom(s) selected from nitrogen,sulfur and oxygen atoms)-carbonyl, mono-C₁₋₆ alkyl-carbamoyl, di-C₁₋₆alkyl-carbamoyl, C₆₋₁₄ aryl-carbamoyl, (5- or 6-membered heterocyclehaving, in addition to carbon atoms, 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms)-carbamoyl, C₁₋₆ alkyl-thiocarbonyl,C₃₋₆ cycloalkyl-thiocarbonyl, C₁₋₆ alkoxy-thiocarbonyl, C₆₋₁₄aryl-thiocarbonyl, C₇₋₁₆ aralkyl-thiocarbonyl, C₆₋₁₄aryloxy-thiocarbonyl, C₇₋₁₆ aralkyloxy-thiocarbonyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbonyl,thiocarbamoyl, mono-C₁₋₆ alkyl-thiocarbamoyl, di-C₁₋₆alkyl-thiocarbamoyl, C₆₋₁₄ aryl-thiocarbamoyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbamoyl,mono-C₁₋₆ alkylsulfamoyl, di-C₁₋₆ alkylsulfamoyl, C₆₋₁₄ arylsulfamoyl,C₁₋₆ alkylsulfonyl, C₆₋₁₄ arylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₄arylsulfinyl, sulfino, sulfo, C₁₋₆ alkoxysulfinyl, C₆₋₁₄aryloxysulfinyl, C₁₋₆ alkoxysulfonyl and C₆₋₁₄ aryloxysulfonyl, whichmay have 1 to 5 substituent(s) selected from Substituent Group Bdescribed above;

[0307] (iv) a group represented by Formula: —OR^(4a)′

[0308] (R^(4a)′ is <1> a hydrogen atom,

[0309] <2> a C₁₋₆ alkyl group, C₃₋₆ cycloalkyl group, C₆₋₁₄ aryl groupor C₇₋₁₆ aralkyl group which may have 1 to 5 substituent(s) selectedfrom Substituent Group B described above, or,

[0310] <3> an acyl group selected from formyl, carboxy, carbamoyl, C₁₋₆alkyl-carbonyl, C₃₋₆ cycloalkyl-carbonyl, C₁₋₆ alkoxy-carbonyl, C₆₋₁₄aryl-carbonyl, C₇₋₁₆ aralkyl-carbonyl, C₆₋₁₄ aryloxy-carbonyl, C₇₋₁₆aralkyloxy-carbonyl, (5- or 6-membered heterocycle having, in additionto carbon atoms, 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms)-carbonyl, mono-C₁₋₆ alkyl-carbamoyl, di-C₁₋₆alkyl-carbamoyl, C₆₋₁₄ aryl-carbamoyl, (5- or 6-membered heterocyclehaving, in addition to carbon atoms, 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms)-carbamoyl, C₁₋₆ alkyl-thiocarbonyl,C₃₋₆ cycloalkyl-thiocarbonyl, C₁₋₆ alkoxy-thiocarbonyl, C₆₋₁₄aryl-thiocarbonyl, C₇₋₁₆ aralkyl-thiocarbonyl, C₆₋₁₄aryloxy-thiocarbonyl, C₇₋₁₆ aralkyloxy-thiocarbonyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbonyl,thiocarbamoyl, mono-C₁₋₆ alkyl-thiocarbamoyl, di-C₁₋₆alkyl-thiocarbamoyl, C₆₋₁₄ aryl-thiocarbamoyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbamoyl,mono-C₁₋₆ alkylsulfamoyl, di-C₁₋₆ alkylsulfamoyl, C₆₋₁₄ arylsulfamoyl,C₁₋₆ alkylsulfonyl, C₆₋₁₄ arylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₄arylsulfinyl, sulfino, sulfo, C₁₋₆ alkoxysulfinyl, C₆₋₁₄aryloxysulfinyl, C₁₋₆ alkoxysulfonyl and C₆₋₁₄ aryloxysulfonyl, whichmay have 1 to 5 substituent(s) selected from Substituent Group Bdescribed above);

[0311] R⁵ is any of the following (i) to (iv):

[0312] (i) a C₁₋₆ alkyl group, C₃₋₆ cycloalkyl group, C₆₋₁₄ aryl groupor C₇₋₁₆ aralkyl group which may have 1 to 5 substituent(s) selectedfrom Substituent Group B described above,

[0313] (ii) an acyl group selected from formyl, carboxy, carbamoyl, C₁₋₆alkyl-carbonyl, C₃₋₆ cycloalkyl-carbonyl, C₁₋₆ alkoxy-carbonyl, C₆₋₁₄aryl-carbonyl, C₇₋₁₆ aralkyl-carbonyl, C₆₋₁₄ aryloxy-carbonyl, C₇₋₁₆aralkyloxy-carbonyl, (5- or 6-membered heterocycle having, in additionto carbon atoms, 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms)-carbonyl, mono-C₁₋₆ alkyl-carbamoyl, di-C₁₋₆ alkylcarbamoyl, C₆₋₁₄ aryl-carbamoyl, (5- or 6-membered heterocycle having,in addition to carbon atoms, 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms)-carbamoyl, C₁₋₆ alkyl-thiocarbonyl,C₃₋₆ cycloalkyl-thiocarbonyl, C₁₋₆ alkoxy-thiocarbonyl, C₆₋₁₄aryl-thiocarbonyl, C₇₋₁₆ aralkyl-thiocarbonyl, C₆₋₁₄aryloxy-thiocarbonyl, C₇₋₁₆ aralkyloxy-thiocarbonyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbonyl,thiocarbamoyl, mono-C₁₋₆ alkyl-thiocarbamoyl, di-C₁₋₆alkyl-thiocarbamoyl, C₆₋₁₄ aryl-thiocarbamoyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbamoyl,mono-C₁₋₆ alkylsulfamoyl, di-C₁₋₆ alkylsulfamoyl, C₆₋₁₄ arylsulfamoyl,C₁₋₆ alkylsulfonyl, C₆₋₁₄ arylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₄arylsulfinyl, sulfino, sulfo, C₁₋₆ alkoxysulfinyl, C₆₋₁₄aryloxysulfinyl, C₁₋₆ alkoxysulfonyl and C₆₋₁₄ aryloxysulfonyl, whichmay have 1 to 5 substituent(s) selected from Substituent Group Bdescribed above,

[0314] (iii) a 5- to 14-membered heterocyclic ring containing 1 to 4heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms which may contain 1 to 5 substituent(s)selected from Substituent Group B described above,

[0315] (iv) a halogen atom;

[0316] each of R^(6a), R^(7a), R^(8a) and R^(9a) is (i) a hydrogen atomor (ii) a C₁₋₆ alkyl group, C₃₋₆ cycloalkyl group, C₆₋₁₄ aryl group orC₇₋₁₆ aralkyl group which may have 1 to 5 substituent(s) selected fromSubstituent Group B described above,

[0317] X^(a) is (i) a bond, (ii) an oxygen atom, (iii) anoptionally-oxidized sulfur atom, (iv) a nitrogen atom which may have aC₁₋₆ alkyl group, C₂₋₆ alkenyl group, C₂₋₆ alkynyl group, C₃₋₆cycloalkyl group, C₃₋₆ cycloalkenyl group, C₆₋₁₄ aryl group or C₇₋₁₆aralkyl group which may have 1 to 5 substituent(s) selected fromSubstituent Group B described above,

[0318] (v) a nitrogen atom having an acyl group selected from formyl,carboxy, carbamoyl, C₁₋₆ alkyl-carbonyl, C₃₋₆ cycloalkyl-carbonyl, C₁₋₆alkoxy-carbonyl, C₆₋₁₄ aryl-carbonyl, C₇₋₁₆ aralkyl-carbonyl, C₆₋₁₄aryloxy-carbonyl, C₇₋₁₆ aralkyloxy-carbonyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-carbonyl, mono-C₁₋₆alkyl-carbamoyl, di-C₁₋₆ alkyl-carbamoyl, C₆₋₁₄ aryl-carbamoyl, (5- or6-membered heterocycle having, in addition to carbon atoms, 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygenatoms)-carbamoyl, C₁₋₆ alkyl-thiocarbonyl, C₃₋₆ cycloalkyl-thiocarbonyl,C₁₋₆ alkoxy-thiocarbonyl, C₆₋₁₄ aryl-thiocarbonyl, C₇₋₁₆aralkyl-thiocarbonyl, C₆₋₁₄ aryloxy-thiocarbonyl, C₇₋₁₆aralkyloxy-thiocarbonyl, (5- or 6-membered heterocycle having, inaddition to carbon atoms, 1 to 3 heteroatom(s) selected from nitrogen,sulfur and oxygen atoms)-thiocarbonyl, thiocarbamoyl, mono-C₁₋₆alkyl-thiocarbamoyl, di-C₁₋₆ alkyl-thiocarbamoyl, C₆₋₁₄aryl-thiocarbamoyl, (5- or 6-membered heterocycle having, in addition tocarbon atoms, 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms)-thiocarbamoyl, mono-C₁₋₆ alkylsulfamoyl, di-C₁₋₆alkylsulfamoyl, C₆₋₁₄ arylsulfamoyl, C₁₋₆ alkylsulfonyl, C₆₋₁₄arylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₄ arylsulfinyl, sulfino, sulfo,C₁₋₆ alkoxysulfinyl, C₆₋₁₄ aryloxysulfinyl, C₁₋₆ alkoxysulfonyl andC₆₋₁₄ aryloxysulfonyl, which may have 1 to 5 substituent(s) selectedfrom Substituent Group B described above, or,

[0319] (vi) a nitrogen atom having a 5- to 14-membered heterocyclicgroup containing 1 to 4 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms in addition to carbon atoms which may contain 1 to 5substituent(s) selected from Substituent Group B described above;

[0320] Z is (i) a group represented by Formula: —OZ^(a)

[0321] (Z^(a) is <1> a hydrogen atom,

[0322] <2> a C₁₋₆ alkyl group, C₂₋₆ alkenyl group, C₂₋₆ alkynyl group,C₃₋₆ cycloalkyl group, C₃₋₆ cycloalkenyl group, C₆₋₁₄ aryl group orC₇₋₁₆ aralkyl group which may have 1 to 5 substituent(s) selected fromSubstituent Group B described above, or,

[0323] <3> an acyl group selected from formyl, carboxy, carbamoyl, C₁₋₆alkyl-carbonyl, C₃₋₆ cycloalkyl-carbonyl, C₁₋₆ alkoxy-carbonyl, C₆₋₁₄aryl-carbonyl, C₇₋₁₆ aralkyl-carbonyl, C₆₋₁₄ aryloxy-carbonyl, C₇₋₁₆aralkyloxy-carbonyl, (5- or 6-membered heterocycle having, in additionto carbon atoms, 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms)-carbonyl, mono-C₁₋₆ alkyl-carbamoyl, di-C₁₋₆alkyl-carbamoyl, C₆₋₁₄ aryl-carbamoyl, (5- or 6-membered heterocyclehaving, in addition to carbon atoms, 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms)-carbamoyl, C₁₋₆ alkyl-thiocarbonyl,C₃₋₆ cycloalkyl-thiocarbonyl, C₁₋₆ alkoxy-thiocarbonyl, C₆₋₁₄aryl-thiocarbonyl, C₇₋₁₆ aralkyl-thiocarbonyl, C₆₋₁₄aryloxy-thiocarbonyl, C₇₋₁₆ aralkyloxy-thiocarbonyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbonyl,thiocarbamoyl, mono-C₁₋₆ alkyl-thiocarbamoyl, di-C₁₋₆alkyl-thiocarbamoyl, C₆₋₁₄ aryl-thiocarbamoyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbamoyl,mono-C₁₋₆ alkylsulfamoyl, di-C₁₋₆ alkylsulfamoyl, C₆₋₁₄ arylsulfamoyl,C₁₋₆ alkylsulfonyl, C₆₋₁₄ arylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₄arylsulfinyl, sulfino, sulfo, C₁₋₆ alkoxysulfinyl, C₆₋₁₄aryloxysulfinyl, C₁₋₆ alkoxysulfonyl and C₆₋₁₄ aryloxysulfonyl, whichmay have 1 to 5 substituent(s) selected from Substituent Group Adescribed above) or (ii) a halogen atom group,

[0324] [61] the compound according to the above-mentioned [59] wherein:

[0325] each of R^(2a) and R^(3a) is (1) a C₁₋₆ alkyl group which may besubstituted by <1> a halogen atom, <2> a hydroxy group which may besubstituted by a substituent selected from a C₁₋₆ alkyl, C₁₋₆alkyl-carbonyl, C₁₋₆ alkylsulfonyl and C₇₋₁₆ aralkyl, <3> an amino groupwhich may be substituted by 1 or 2 C₁₋₆ alkyl, C₁₋₆ alkyl-carbonyl andC₆₋₁₄ aryl-carbonyl, <4> a 4- to 10-membered heterocyclic groupcontaining 1 to 3 heteroatom(s) selected from nitrogen, oxygen andsulfur atoms in addition to carbon atoms, <5> a thio group which may besubstituted by C₁₋₆ alkyl, <6> a C₁₋₆ alkyl-sulfinyl group or <7> a C₁₋₆alkyl-sulfonyl group or (2) a C₁₋₆ alkoxy-carbonyl group,

[0326] R^(4a) is (i) a hydrogen atom, (ii) a C₁₋₆ alkyl group [this C₁₋₆alkyl group may have a substituent selected from (1) a halogen atom, (2)a C₁₋₆ alkoxy group, (3) a hydroxy group, (4) an amino group, (5) amono-C₁₋₆ alkylamino group, (6) a di-C₁₋₆ alkylamino group, (7) a 4- to10-membered heterocyclic group containing 1 to 3 heteroatom(s) selectedfrom nitrogen, sulfur and oxygen atoms in addition to-carbon atoms whichmay have an oxo, (8) a C₆₋₁₄ arylthio, (9) an ureido, (10) a carboxy,(11) a carbamoyl, (12) a C₁₋₆ alkoxy-carbonyl, (13) a mono-C₁₋₆alkyl-carbamoyl, (14) a formylamino and (15) a C₁₋₆ alkyl-carboxamido]or (iii) a formyl group;

[0327] X^(a) is a bond, oxygen atom, optionally oxidized sulfur atom,—NH—or —N(methyl)-,

[0328] R^(5a) is,

[0329] when X^(a) is a bond, then (i) a C₁₋₆ alkyl group or (ii) ahalogen atom,

[0330] when X^(a) is an oxygen atom, then (i) a C₁₋₆ alkyl group [thisC₁₋₆ alkyl group may have a substituent selected from (1) a halogenatom, (2) a hydroxy group, (3) an amino group, (4) a carboxy, (5) acarbamoyl, (6) a C₁₋₆ alkoxy-carbonyl, (7) a mono-C₁₋₆ alkyl-carbamoyl,(8) a di-C₁₋₆ alkyl-carbamoyl, (9) a 4- to 10-membered heterocyclicgroup containing 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms in addition to carbon atoms], (ii) a C₃₋₆ cycloalkyl group,(iii) a C₇₋₁₆ aralkyl group, (iv) a C₁₋₆ alkyl-carbonyl group, (v) aC₆₋₁₄ aryl-carbonyl group, (vi) a C₁₋₆ alkoxy-carbonyl group, (vii) amono- or di-C₁₋₆ alkyl-thiocarbamoyl group, (viii) an optionallyhalogenated C₁₋₆ alkyl-sulfonyl group or (ix) a 4- to 10-memberedheterocyclic group containing 1 to 4 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms in addition to carbon atoms [thisheterocyclic group may have a C₆₋₁₄ aryl],

[0331] when X^(a) is an optionally oxidized sulfur, then (i) a C₁₋₆alkyl group or (ii) a mono- or di-C₁₋₆ alkyl-carbamoyl group,

[0332] when X^(a) is —NH—or —N(methyl)-, then (i) a C₁₋₆ alkyl group[this C₁₋₆ alkyl group may have a C₁₋₆ alkoxy-carbonyl], (ii) formyl,(iii) a C₁₋₆ alkyl-carbonyl group, (iv) a C₁₋₆ alkoxy-carbonyl group,(v) a carbamoyl group, (vi) a mono- or di-C₁₋₆ alkyl-carbamoyl group or(vii) a C₁₋₆ alkyl-sulfonyl group,

[0333] each of R^(6a), R^(7a), R^(8a) and R^(9a) is a hydrogen atom orC₁₋₆ alkyl group,

[0334] Z is (i) a hydroxy group which may be substituted by a C₁₋₆alkyl-carbonyl or (ii) a halogen atom, [62] a use of the compoundaccording to the above-mentioned [59] or a salt thereof for producingthe compound according to the above-mentioned [2] or a salt thereof.

[0335] Furthermore, the invention also provides:

[0336] [63] a compound having a partial structure represented byFormula:

[0337] wherein each of Ring A, Ring B and Ring C may have substituentsor a salt thereof,

[0338] [64] the compound according to the above-mentioned [63] whereinthe substituents on Ring A, Ring B and Ring C are 1 to 5 substituent(s)selected from the group consisting of (1) an optionally substitutedhydrocarbon group, (2) an optionally substituted heterocyclic group, (3)an optionally substituted amino group, (4) an acyl group, (5) anoptionally substituted hydroxy group, (6) an optionally substitutedsulfenyl group, (7) a halogen atom, (8) a lower alkylenedioxy group, (9)a nitro group, (10) a cyano group, (11) an optionally substituted iminogroup, (12) an oxo group, (13) an optionally substituted ureido group,(14) an azide group, (15) an optionally substituted amidino group, (16)an optionally substituted guanidino group, (17) an optionallysubstituted hydrazino group and (18) an oxide group,

[0339] [65] the compound according to the above-mentioned [64], in whichthe substituent is a group selected from Substituent Group A,

[0340] [66] the pharmaceutical composition according to theabove-mentioned [23] wherein Compound (A-1) is a compound represented byFormula:

[0341] wherein - - - is a single bond or double bond and each of Ring A,Ring B and Ring C may have substituent(s) or a salt thereof,

[0342] [67] the pharmaceutical composition according to theabove-mentioned [23] wherein Compound (A-1) is a compound represented byFormula:

[0343] wherein - - - is a single bond or double bond and other symbolsare defined as described in claim 2.

[0344] Furthermore, when any of Compounds (A), (I), (I′), (A-1), (I-1),(I′-1) or their salts contains asymmetric carbon atom in its structure,any of the optically active forms and racemic forms is encompassed inthe invention, and Compounds (A), (I), (I′), (A-1), (I-1), (I′-1) ortheir salts may be hydrates or anhydrides.

BEST MODE FOR EMBODYING THE INVENTION

[0345] A compound according to the invention has a partial structurerepresented by Formula:

[0346] which is represented typically by Formula:

[0347] wherein each symbol is defined as described above.

[0348] In the formula shown above, each of Ring A, Ring B and Ring C mayhave a substitutable number of substituents in any substitutablepositions.

[0349] Each of such substituents on Ring A, Ring B and Ring C is:

[0350] (1) an optionally substituted hydrocarbon group,

[0351] (2) an optionally substituted heterocyclic group,

[0352] (3) an optionally substituted amino group,

[0353] (4) an acyl group,

[0354] (5) an optionally substituted hydroxy group,

[0355] (6) an optionally substituted sulfinyl group,

[0356] (7) a halogen atom (for example, fluorine, chlorine, bromine,iodine),

[0357] (8) a lower alkylenedioxy group (for example, a C₁₋₃alkylenedioxy group such as methylenedioxy, ethylenedioxy, etc.),

[0358] (9) a nitro group,

[0359] (10) a cyano group,

[0360] (11) an optionally substituted imino group,

[0361] (12) an oxo group,

[0362] (13) an optionally substituted ureido group,

[0363] (14) an azide group,

[0364] (15) an optionally substituted amidino group,

[0365] (16) an optionally substituted guanidino group,

[0366] (17) an optionally substituted hydrazino group,

[0367] (18) an oxide group and the like.

[0368] A hydrocarbon group in an “optionally substituted hydrocarbongroup” employed as a substituent on Ring A, Ring B and Ring C may forexample be a linear or cyclic hydrocarbon group such as an alkyl group,alkenyl group, alkynyl group, cycloalkyl group, aryl group and aralkylgroup, with a linear (straight or branched) or cyclic hydrocarbon grouphaving 1 to 16 carbon atoms (e.g., aromatic hydrocarbon group, aliphaticcyclic hydrocarbon group) being preferred. Typically, those listed beloware employed.

[0369] (1) Linear hydrocarbon groups:

[0370] a) alkyl groups [preferably, lower alkyl groups (for example,C₁₋₆ alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.)],

[0371] b) alkenyl groups [preferably, lower alkenyl groups (for example,C₂₋₆ alkenyl groups such as vinyl, allyl, isopropenyl, 2-butenyl,2-methyl-2-propenyl, 4-pentenyl, 5-hexenyl, etc.)],

[0372] c) alkynyl groups [preferably, lower alkynyl groups (for example,C₂₋₆ alkynyl groups such as propargyl, ethynyl, 2-butynyl, 2-hexynyl)],

[0373] (2) Aliphatic cyclic hydrocarbon groups:

[0374] a) cycloalkyl groups [preferably, lower cycloalkyl group (forexample, C₃₋₆ cycloalkyl groups such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, etc.), each of which may be fused with abenzene ring],

[0375] b) cycloalkenyl groups [preferably, lower cycloalkenyl group (forexample, C₃₋₆ cycloalkenyl groups such as 1-cyclopropenyl,1-cyclobutenyl, 1-cyclopentenyl, 1-cyclohexenyl, etc.), each of whichmay be fused with a benzene ring],

[0376] (3) Aromatic hydrocarbon groups:

[0377] aryl groups (for example, C₆₋₁₄ aryl groups such as phenyl,1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl,2-phenanthryl, 3-phenanthryl, 4-phenanthryl or 9-phenanthryl, preferablyphenyl group),

[0378] (4) Aralkyl groups:

[0379] lower aralkyl groups (for example, C₇₋₁₆ aralkyl groups such asbenzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl,2-phenethyl, 2,2-diphenylethyl, 1-phenylpropyl, 2-phenylpropyl,3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, preferably benzyl group).

[0380] A substituent on each of the hydrocarbon groups listed abovewhich is employed preferably may for example be 1 to 5, preferably 1 to3 group(s) selected from the group (Substituent Group A) consisting of(1) a halogen atom (for example, fluorine, chlorine, bromine, iodine),(2) a lower alkylenedioxy group (for example, a C₁₋₃ alkylene dioxygroup such as methylenedioxy, ethylenedioxy, etc.), (3) a nitro group,(4) a cyano group, (5) an optionally halogenated lower alkyl group, (6)an optionally halogenated lower alkenyl group, (7) an optionallyhalogenated lower alkynyl group, (8) a lower cycloalkyl group (forexample, a C₃₋₆ cycloalkyl group such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, etc.), (9) a C₆₋₁₄ aryl group (e.g., phenyl,2-naphthyl, etc.), (10) an optionally halogenated lower alkoxy group,(11) an optionally halogenated lower alkylthio group, (12) a hydroxygroup, (13) an amino group, (14) a mono-lower alkylamino group (e.g.,mono-C₁₋₆ alkylamino group such as methylamino, ethylamino, propylamino,isopropylamino, butylamino, etc.), (15) a mono-C₆₋₁₄ arylamino group(e.g., phenylamino, 2-naphthylamino, etc.), (16) di-lower alkylaminogroup (e.g., di-Cl6 alkylamino group such as dimethylamino,diethylamino, dipropylamino, dibutylamino, ethylmethylamino, etc.), (17)a di-C₆₋₁₄ arylamino group (e.g., diphenylamino, di(2-naphthyl)amino,etc.), (18) an acyl group, (19) an acylamino group, (20) an acyloxygroup, (21) a 4- to 14-membered heterocyclic group (preferably 4- to10-membered, more preferably 4- to 7-membered, especially 5- or6-membered heterocyclic group) (e.g., 4- to 10-membered, more preferably4- to 7-membered, especially 5- or 6-membered heterocyclic groupcontaining 1 to 4 heteroatom(s) selected from nitrogen, sulfur, oxygenatoms and the like in addition to carbon atoms, such as 4-pyridyl,2-thienyl, 2-furyl, 2-thiazolyl, 3-indolyl, morpholino, piperazin-1-yl,piperidino, pyrrolidin-1-yl, 2-isoindolinyl, etc.), (22) a phosphonogroup, (23) a C₆₋₁₄ aryloxy group (e.g., phenoxy), (24) a di-C₁₋₆alkoxyphosphoryl group (e.g., dimethoxyphosphoryl, diethoxyphosphoryl,etc.), (25) a C₆₋₁₄ arylthio group (e.g., phenylthio), (26) a hydrazinogroup, (27) an imino group, (28) an oxo group, (29) an ureido group,(30) a C₁₋₆ alkyl-ureido group (e.g., methylureido, ethylureido), (31) adi-C₁₋₆ alkyl-ureido group (e.g., dimethylureido, diethylureido, etc.),(32) an oxide group, (33) a group formed by binding 2 or 3 groupsselected from (1) to (32) listed above.

[0381] An “optionally halogenated lower alkyl group” in SubstituentGroup A described above may for example be a lower alkyl group which mayhave 1 to 3 halogen atom(s) (for example, fluorine, chlorine, bromine,iodine) (for example, a C₁₋₆ alkyl group such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.),and those exemplified typically are methyl, chloromethyl,difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl,2,2,2-trifluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl,4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyland the like.

[0382] An “optionally halogenated lower alkenyl group” in SubstituentGroup A described above may for example be a lower alkenyl group whichmay have 1 to 3 halogen atom(s) (for example, fluorine, chlorine,bromine, iodine) (for example, a C₂₋₆ alkenyl group such as vinyl,allyl, isopropenyl, 2-butenyl, 2-methyl-2-propenyl, 4-pentenyl,5-hexenyl, etc.).

[0383] An “optionally halogenated lower alkynyl group” in SubstituentGroup A described above may for example be a lower alkynyl group whichmay have 1 to 3 halogen atom(s) (for example, fluorine, chlorine,bromine, iodine) (for example, a C₂₋₆ alkynyl group such as propargyl,ethynyl, 2-butynyl, 2-hexynyl).

[0384] An “optionally halogenated lower alkoxy group” in SubstituentGroup A described above may for example be a lower alkoxy group whichmay have 1 to 3 halogen atom(s) (e.g., fluorine, chlorine, bromine,iodine) (for example, a C₁₋₆ alkoxy group such as methoxy, ethoxy,propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy,pentyloxy, isopentyloxy, neopentyloxy, etc.), and those exemplifiedtypically are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, tert-butoxy, trichloromethoxy, 3,3,3-trifluoropropoxy,4,4,4-trifluorobutoxy, 5,5,5-trifluoropentyloxy, 6,6,6-trifluorohexyloxyand the like.

[0385] An “optionally halogenated lower alkylthio group” in SubstituentGroup A described above may for example be a C₁₋₆ alkylthio group whichmay have 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine,iodine) (for example, a C₁₋₆ alkylthio group such as methylthio,ethylthio, propylthio, isopropylthio, butylthio, isobutylthio,sec-butylthio, tert-butylthio, etc.), and those exemplified typicallyare methylthio, difluoromethylthio, trifluoromethylthio, ethylthio,propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio,pentylthio, hexylthio and the like.

[0386] An “acyl group” in Substituent Group A employed preferably mayfor example be formyl, carboxy, carbamoyl, C₁₋₆ alkyl-carbonyl (e.g.,acetyl, propionyl, etc.), C₃₋₆ cycloalkyl- carbonyl (e.g.,cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), C₁₋₆ alkoxy-carbonyl(e.g., methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl,tert-butoxycarbonyl, etc.), C₆₋₁₄ aryl-carbonyl (e.g., benzoyl,2-naphthoyl, etc.), C₇₋₁₆ aralkyl-carbonyl (e.g., phenylacetyl,3-phenylpropionyl, etc.), C₆₋₁₄ aryloxy-carbonyl (e.g., phenoxycarbonyl,2-naphthyloxycarbonyl), C₇₋₁₆ aralkyloxy-carbonyl (e.g.,benzyloxycarbonyl, 2-naphthylmethyloxycarbonyl, etc.), 5- or 6-memberedheterocyclic carbonyl (e.g., (5- or 6-membered heterocyclic groupcontaining 1 to 3 heteroatom(s) selected from nitrogen, sulfur, oxygenatoms and the like in addition to carbon atoms)-carbonyl such as1-pyrrolidinylcarbonyl, 4-piperidylcarbonyl, 1-piperazinylcarbonyl,2-morpholinylcarbonyl, 4-pyridylcarbonyl, 3-thienylcarbonyl,2-furylcarbonyl, 2-thiazolylcarbonyl, etc.), mono-C₁₋₆ alkyl-carbamoyl(e.g., methylcarbamoyl, ethylcarbamoyl, etc.), di-C₁₋₆ alkyl-carbamoyl(e.g., dimethylcarbamoyl, diethylcarbamoyl, etc.), C₆₋₁₄ aryl-carbamoyl(e.g., phenylcarbamoyl, 2-naphthylcarbamoyl), 5-or 6-memberedheterocyclic carbamoyl (e.g., (5- or 6-membered heterocyclic groupcontaining 1 to 3 heteroatom(s) selected from nitrogen, sulfur, oxygenatoms and the like in addition to carbon atoms)-carbamoyl such as1-pyrrolidinylcarbamoyl, 4-piperidylcarbamoyl, 1-piperazinylcarbamoyl,2-morpholinylcarbamoyl, 4-pyridylcarbamoyl, 3-thienylcarbamoyl,2-furylcarbamoyl, 2-thiazolylcarbamoyl, etc.), C₁₋₆ alkyl-thiocarbonyl(e.g., methylthiocarbonyl, etc.), C₃₋₆ cycloalkyl-thiocarbonyl (e.g.,cyclopentylthiocarbonyl, cyclohexylthiocarbonyl, etc.), C₁₋₆alkoxy-thiocarbonyl (e.g., methoxythiocarbonyl, methoxythiocarbonyl,propoxythiocarbonyl, butoxythiocarbonyl, etc.), C₆₋₁₄ aryl-thiocarbonyl(e.g., phenylthiocarbonyl, 2-naphthylthiocarbonyl, etc.), C₇₋₁₆aralkyl-thiocarbonyl (e.g., benzylthiocarbonyl, phenethylthiocarbonyl),C₆₋₁₄ aryloxy-thiocarbonyl (e.g., phenoxythiocarbonyl,2-naphthyloxythiocarbonyl), C₇₋₁₆ aralkyloxy-thiocarbonyl, (e.g.,benzyloxythiocarbonyl, 2-naphthylmethyloxythiocarbonyl), 5- or6-membered heterocyclic thiocarbonyl, (e.g., (5- or 6-memberedheterocyclic group containing 1 to 3 heteroatom(s) selected fromnitrogen, sulfur, oxygen atoms and the like in addition to carbonatoms)-thiocarbonyl such as 1-pyrrolidinylthiocarbonyl,4-piperidylthiocarbonyl, 1-piperazinylthiocarbonyl,2-morpholinylthiocarbonyl, 4-pyridylthiocarbonyl, 3-thienylthiocarbonyl,2-furylthiocarbonyl, 2-thiazolylthiocarbonyl, etc.), thiocarbamoyl,mono-C₁₋₆ alkyl-thiocarbamoyl (e.g., methylthiocarbamoyl,ethylthiocarbamoyl), di-C₁₋₆ alkyl-thiocarbamoyl (for example,dimethylthiocarbamoyl, diethylthiocarbamoyl), C₆₋₁₄ aryl-thiocarbamoyl(e.g., phenylthiocarbamoyl, 2-naphthylthiocarbamoyl), sulfamoyl,mono-C₁₋₆ alkyl-sulfamoyl (e.g., methylsulfamoyl, ethylsulfamoyl),di-C₁₋₆ alkyl-sulfamoyl (e.g., dimethylsulfamoyl, diethylsulfamoyl,etc.), C₆₋₁₄ aryl-sulfamoyl (e.g., phenylsulfamoyl), C₁₋₆ alkylsulfonyl(e.g., methylsulfonyl, ethylsulfonyl, etc.), C₆₋₁₄ arylsulfonyl (e.g.,phenylsulfonyl, 2-naphthylsulfonyl), C₁₋₆ alkylsulfinyl (e.g.,methylsulfinyl, ethylsulfinyl), C₆₋₁₄ arylsulfinyl (e.g.,phenylsulfinyl, 2-naphthylsulfinyl, etc.), sulfino, sulfo, C₁₋₆alkoxysulfinyl (e.g., methoxysulfinyl, ethoxysulfinyl), C₆₋₁₄aryloxysulfinyl (e.g., phenoxysulfinyl), C₁₋₆ alkoxysulfonyl (e.g.,methoxysulfonyl, ethoxysulfonyl) and C₆₋₁₄ aryloxysulfonyl (e.g.,phenoxysulfonyl). Among those listed above, a C₁₋₇ acyl group such asformyl, carboxy, C₁₋₆ alkyl-carbonyl, C₁₋₆ alkoxy-carbonyl, carbamoyl,mono-C₁₋₆ alkylcarbamoyl, sulfamoyl and mono-C₁₋₆ alkyl-sulfamoyl ispreferred.

[0387] An “acylamino group” in Substituent Group A may for example beformylamino, optionally halogenated C₁₋₆ alkyl-carboxamido (e.g.,acetamido, propionamido, 2-chloroacetamido, 2,2-dichloroacetamido,2,2,2-trichloroacetamido, etc.), C₆₋₁₄ aryl-carboxamido (e.g.,benzamido, 2-naphthylcarboxamido, etc.), C₁₋₆ alkoxy-carboxamido (e.g.,methoxycarboxamido, ethoxycarboxamido, isopropoxycarboxamido,tert-butoxycarboxamido, etc.), C₁₋₆ alkylsulfonylamino (e.g.,methylsulfonylamino, ethylsulfonylamino, etc.), bis(C₁₋₆alkylsulfonyl)amino (e.g., bis(methylsulfonyl)amino,bis(ethylsulfonyl)amino), C₆₋₁₄ arylsulfonylamino (e.g.,phenylsulfonylamino, 2-naphthylsulfonylamino, etc.) and the like. Amongthose listed above, a C₁₋₇ acylamino group such as formylamino,optionally halogenated C₁₋₆ alkyl-carboxamido, C₁₋₆ alkoxy-carboxamido,C₁₋₆ alkylsulfonylamino and bis(C₁₋₆ alkylsulfonyl)amino is preferred.

[0388] An “acyloxy group” in Substituent Group A described above may forexample be a C₁₋₆ alkyl-carbonyloxy (e.g., acetyloxy, propionyloxy,etc.), C₆₋₁₄ aryl-carbonyloxy (e.g., benzoyloxy, 2-naphthoyloxy, etc.),C₁₋₆ alkoxy-carbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy,isopropoxycarbonyloxy, tert-butoxycarbonyloxy, etc.), mono-C₁₋₆alkyl-carbamoyloxy (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, etc.),di-C₁₋₆ alkyl-carbamoyloxy (e.g., dimethylcarbamoyloxy,diethylcarbamoyloxy, etc.) and C₆₋₁₄ aryl-carbamoyloxy (e.g.,phenylcarbamoyloxy, 2-naphthylcarbamoyloxy, etc.). Among those listedabove, a C₂₋₇ acyloxy such as a C₁₋₆ alkyl-carbonyloxy and C₁₋₆alkoxy-carbonyloxy is preferred.

[0389] A group formed by binding 2 or 3 groups selected from (1) to (32)listed above in Substituent Group A described above may for example be:

[0390] (33a) a substituted C₁₋₆ alkyl group [this C₁₋₆ alkyl group has asubstituent selected from cyano, carbamoyl, C₁₋₆ alkyl-carbamoyl, C₁₋₆alkyl-carbonyloxy, C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkyl-carbamoyl, 5- or6-membered heterocyclic ring (e.g., 5- or 6-membered heterocyclic ringcontaining 1 to 3 heteroatom(s) selected from nitrogen, sulfur, oxygenatoms and the like in addition to carbon atoms such as pyridyl,etc.)-C₁₋₆ alkyl-carbamoyl, C₁₋₆ alkylsulfonylamino, C₁₋₆alkoxy-carbonyl and carboxy, etc.],

[0391] (33b) a substituted C₆₋₁₄ aryl group [this C₆₋₁₄ aryl group has asubstituent selected from amino, optionally halogenated C₁₋₆alkyl-carbonylamino, ureido, C₁₋₆ alkylsulfonylamino, (C₁₋₆ alkyl)(C₁₋₆alkylsulfonyl)amino and C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkylamino, etc.],

[0392] (33c) a C₁₋₆ alkoxy-C₆₋₁₄ aryl-C₁₋₆ alkoxy group,

[0393] (33d) a 5- to 14-membered heterocyclic group containing 1 to 4heteroatom(s) selected from nitrogen, sulfur, oxygen atoms and the likein addition to carbon atoms which has a substituent [this heterocyclicgroup has a substituent selected from oxo, carboxy-C₁₋₆ alkyl, C₁₋₆alkyl-carbonyloxy-C₁₋₆ alkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy-carbonyl-C₁₋₆alkyl and C₁₋₆ alkyl-carbamoyl-C₁₋₆ alkyl],

[0394] (33e) a group represented by Formula: —NR¹²R¹³

[0395] [each of R¹² and R¹³ is (i) a 5- or 6-membered heterocyclic ring(e.g., 5- or 6-membered heterocyclic ring containing 1 to 3heteroatom(s) selected from nitrogen, sulfur, oxygen atoms and the likein addition to carbon atoms)-C₁₋₆ alkyl, (ii) a C₁₋₆alkoxy-carbonyl-C₁₋₆ alkyl, (iii) a di-C₁₋₆alkylamino-methylene-sulfamoyl-C₁₋₆ alkyl, (iv) a carbamoyl-C₁₋₆ alkyl,(v) a sulfamoyl-C₁₋₆ alkyl, (vi) a C₁₋₆ alkyl-sulfonyl, (vii) a C₁₋₆alkoxy-carbonyl, (viii) di-C₁₋₆ alkoxy-carbonyl-C₂₋₆ alkenyl, (ix) a 5-or 6-membered heterocyclic ring (e.g., 5- or 6-membered heterocyclicgroup containing 1 to 3 heteroatom(s) selected from nitrogen, sulfur,oxygen atoms and the like in addition to carbon atoms) [this 5- or6-membered heterocyclic group may have a substituent selected fromamino, C₁₋₆ alkyl-carboxamido, C₁₋₆ alkyl-sulfonylamino and the like],(x) an optionally halogenated C₁₋₆ alkyl-carbonyl, (xi) a C₁₋₆alkylthio-C₁₋₆ alkyl-carbonyl, (xii) a C₁₋₆ alkylsulfinyl-C₁₋₆alkyl-carbonyl, (xiii) a C₁₋₆ alkylsulfonyl-C₁₋₆ alkyl-carbonyl, (xiv)an amino-C₁₋₆ alkyl-carbonyl, (xv) an optionally halogenated C₁₋₆alkyl-carbonyl-amino-C₁₋₆ alkyl-carbonyl, (xvi) a C₆₋₁₄ aryl-carbonyl(xvii) a carboxy-C₆₋₁₄ aryl-carbonyl, (xviii) an optionally C₁₋₆alkyl-esterified phosphono-C₁₋₆ alkyl-C₆₋₁₄ aryl-carbonyl, (xix) (5- or6-membered heterocyclic ring (e.g., 5- or 6-membered heterocyclic groupcontaining 1 to 3 heteroatom(s) selected from nitrogen, sulfur, oxygenatoms and the like in addition to carbon atoms) which may have a C₁₋₆alkoxy-carbonyl)-carbonyl, (xx) a 5- or 6-membered heterocyclic ring(e.g., 5- or 6-membered heterocyclic group containing 1 to 3heteroatom(s) selected from nitrogen, sulfur, oxygen atoms and the likein addition to carbon atoms)-C₁₋₆ alkyl-carbonyl, (xxi) a C₆₋₁₄aryl-oxy-carbonyl, (xxii) a carboxy-C₁₋₆ alkyl, (xxiii) a carbamoyl andthe like],

[0396] (33f) a group represented by Formula: —CO-Hal (Hal is a halogenatom),

[0397] (33g) a substituted sulfamoyl group [this sulfamoyl group has asubstituent selected from carbamoyl-C₁₋₆ alkyl, (5- or 6-memberedheterocyclic ring)-C₁₋₆ alkyl],

[0398] (33h) a group represented by Formula: —C(═O)NR¹⁴R¹⁵

[0399] [each of R¹⁴ and R¹⁵ is (i) a (5- or 6-membered heterocyclic ring(e.g., 5- or 6-membered heterocyclic ring containing 1 to 3heteroatom(s) selected from nitrogen, sulfur, oxygen atoms and the likein addition to carbon atoms such as pyridyl, imidazolyl, etc.))-C₁₋₆alkyl, (ii) a carboxy-C₁₋₆ alkyl, (iii) a C₁₋₆ alkoxy-carbonyl-C₁₋₆alkyl-, (iv) a di-C₁₋₆ alkylamino-C₁₋₆ alkyl, (v) a carbamoyl-C₁₋₆alkyl, (vi) a C₁₋₆ alkylcarbamoyl-C₁₋₆ alkyl, (vii) a (5- or 6-memberedheterocyclic ring (e.g., 5- or 6-membered heterocyclic ring containing 1to 3 heteroatom(s) selected from nitrogen, sulfur, oxygen atoms and thelike in addition to carbon atoms such as pyridyl))-C₁₋₆alkylcarbamoyl-C₁₋₆ alkyl, (viii) a (5- or 6-membered heterocyclic ring(e.g., 5- or 6-membered heterocyclic ring containing 1 to 3heteroatom(s) selected from nitrogen, sulfur, oxygen atoms and the likein addition to carbon atoms such as pyridyl))-amino-C₁₋₆ alkyl, (ix) asulfamoyl-C₆₋₁₄ aryl-C₁₋₆ alkyl, (x) a C₆₋₁₄ aryl which may have a C₁₋₆alkoxy, (xi) an optionally C₁₋₆ alkyl-esterified phosphono-C₁₋₆alkyl-C₆₋₁₄ aryl, (xii) a 4- to 10-membered heterocyclic group (e.g., 4-to 10-membered heterocyclic ring containing 1 to 3 heteroatom(s)selected from nitrogen, sulfur, oxygen atoms and the like in addition tocarbon atoms) [this 4- to 10-membered heterocyclic group may have 1 to 2substituent(s) selected from a halogen atom, C₁₋₆ alkyl, oxo and thelike], (xiii) a C₆₋₁₄ aryl-carbamoyl-C₁₋₆ alkyl and the like. As R¹⁴ , ahydrogen atom is preferred].

[0400] An “optionally substituted heterocyclic group” employed as asubstituent on Ring A, Ring B and Ring C may for example be a 4- to14-membered heterocyclic group containing 1 to 4 (preferably 1 to 3)heteroatom(s) selected from nitrogen, sulfur, oxygen atoms and the likein addition to carbon atoms, and those exemplified typically are (a) a4- to 14-membered aromatic heterocyclic group, (b) a 4- to 14-memberedaliphatic heterocyclic group, (c) a bicyclic or tricyclic fused cyclicgroup of 4- to 14-membered heterocyclic ring(s) with benzene ring(s) andthe like.

[0401] Said 4- to 14-membered aromatic heterocyclic group may forexample be a 4- to 14-membered aromatic heterocyclic group containing 1to 4 (preferably 1 to 3) heteroatom(s) selected from nitrogen, sulfur,oxygen atoms and the like in addition to carbon atoms, and thoseexemplified typically are thiophene, furan, indolizine, pyrrole,imidazole, triazole, thiazole, oxazole, pyrazole, pyridine,pyridine-N-oxide, pyrazine, pyrimidine, pyridazine, purine,4H-quinolizine, naphthyridine, isothiazole, isoxazole, furazane, etc.Among them, pyridine, thiophene, furan, etc. are preferred.

[0402] Said 4- to 14-membered aliphatic heterocyclic group may forexample be a 4- to 14-membered aliphatic heterocyclic group containing 1to 4 (preferably 1 to 3) heteroatom(s) selected from nitrogen, sulfur,oxygen atoms and the like in addition to carbon atoms, and thoseexemplified typically are pyrrolidine, piperidine, piperazine,morpholine, thiomorpholine, 1,2-dihydropyridine, imidazolidine and thelike.

[0403] Said bicyclic or tricyclic fused cyclic group of 4- to14-membered heterocyclic ring(s) with benzene ring(s) may for example bea bicyclic or tricyclic fused cyclic group each containing 1 to 4(preferably 1 to 3) heteroatom(s) selected from nitrogen, sulfur, oxygenatoms and the like in addition to carbon atoms with benzene rings, andthose exemplified typically are benzo[b]thiophene, benzofuran,1H-benzimidazole, benzoxazole, benzothiazole, 1,2-benzisothiazole,naphtho[2,3-b]thiophene, thianthrene, xanthene, phenoxathiin, indole,isoindole, 1H-indazole, isoquinoline, quinoline, phthalazine,quinoxaline, quinazoline, cinnoline, carbazole, β-carboline,phenanthridine, acridine, phenazine, phenothiazine, phenoxazine,isochroman, dihydrobenzofuran and the like.

[0404] Substituents on any of the heterocyclic groups listed above maybe 1 to 5, preferably 1 to 3 group(s) selected from Substituent Group Adescribed above.

[0405] An “optionally substituted amino group” employed as a substituenton Ring A, Ring B and Ring C may for example be an amino group which mayhave 1 or 2 substituent(s) selected from an “optionally substitutedhydrocarbon group” described above, an “optionally substitutedheterocyclic group” described above and an “acyl group” in SubstituentGroup A (this “acyl group” may further have 1 to 5, preferably 1 to 3substituent(s) selected from Substituent Group A).

[0406] An “acyl group” as a substituent on Ring A, Ring B and Ring C isone similar to an “acyl group” in Substituent Group A described above.Such an “acyl group” may further have 1 to 5, preferably 1 to 3substituent(s) selected from Substituent Group A.

[0407] A substituent on an “optionally substituted oxy group”,“optionally substituted sulfinyl group”, “optionally substituted iminogroup”, “optionally substituted ureido group”, “optionally substitutedamidino group”, “optionally substituted guanidino group” and “optionallysubstituted hydrazino group” employed as a substituent on Ring A, Ring Band Ring C is an “ optionally substituted hydrocarbon group” describedabove, an “optionally substituted heterocyclic group” described aboveand an “acyl group” in Substituent Group A (this “acyl group” mayfurther have 1 to 5, preferably 1 to 3 substituent(s) selected fromSubstituent Group A).

[0408] A compound in which each of Ring A, Ring B and Ring C has asubstituent is typically a compound represented by Formula:

[0409] wherein each symbol is defined as described above.

[0410] In the formula shown above, R¹ is (1) a hydrogen atom, (2) anoptionally substituted hydrocarbon group, (3) an optionally substitutedheterocyclic group or (4) an optionally substituted amino group.

[0411] An “optionally substituted hydrocarbon group” represented by R¹may be one similar to an “optionally substituted hydrocarbon group”exemplified as a substituent on Ring A.

[0412] An “optionally substituted heterocyclic group” represented by R¹may be one similar to an “optionally substituted heterocyclic group”exemplified as a substituent on Ring A.

[0413] An “optionally substituted amino group” represented by R¹ may beone similar to an “optionally substituted amino group” exemplified as asubstituent on Ring A.

[0414] Preferably, R¹ is (1) an optionally substituted aromatichydrocarbon group, (2) an optionally substituted heterocyclic group, (3)an optionally substituted alicyclic hydrocarbon group, (4) a grouprepresented by Formula: —L—R^(1a) wherein L is methylene, carbonyl or anoptionally substituted nitrogen atom, R^(1a) is a hydrogen atom,optionally substituted aromatic group, optionally substituted hydroxygroup or optionally substituted amino group.

[0415] Each of an “optionally substituted aromatic hydrocarbon group”and “optionally substituted heterocyclic group” is preferably a grouprepresented by Formula:

[0416] wherein R^(1b) is a hydrogen atom, optionally substitutedhydrocarbon group or optionally substituted heterocyclic group, Ring Dis an optionally substituted aromatic hydrocarbon ring or optionallysubstituted heterocyclic ring, E is a bond, methylene, oxygen atom,optionally oxidized sulfur atom, optionally substituted nitrogen atom orgroup represented by Formula :—CS—O—, —CO—O—, —S—CO—, —(CH₂)_(k)—CO—,—NR^(1c)—CO—(CH₂)_(m)—, —NR^(1c) —SO₂—(CH₂)_(m)—,—SO₂—NR^(1c)—(CH₂)_(m)—, —O—CS—NR^(1c)—(CH₂)_(m)—,—NR^(1c)—CO—NR^(1c)—(CH₂)_(m)—, —NR^(1c)—CO—CH₂—(CH₂)_(m)—NR^(1c)—

[0417] wherein R^(1c) is a hydrogen atom, optionally substituted alkylgroup or acyl group, k is 0 or 1, m is an integer of 0 to 3, or a grouprepresented by Formula:

[0418] wherein Hal is a halogen atom, Ring D is defined as describedabove.

[0419] An “aromatic hydrocarbon group” as a preferred group of R¹ mayfor example be a monocyclic or fused polycyclic aromatic hydrocarbongroup having 6 to 14 carbon atoms (C₆₋₁₄ aryl group). Preferably, aC₆₋₁₄ aryl may for example be phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl,2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl,4-phenanthryl, 9-phenanthryl and the like, with phenyl, 1-naphthyl and2-naphthyl, especially phenyl being preferred especially.

[0420] As substituents on this “aromatic hydrocarbon group”, 1 to 5,preferably 1 to 3 groups selected from Substituent Group A are employed.Among such substituents, one employed preferably is:

[0421] (1) a halogen atom,

[0422] (2) a nitro group,

[0423] (3) a C₁₋₆ alkyl group (methyl, isopropyl, tert-butyl and thelike),

[0424] [this C₁₋₆ alkyl group may have a substituent selected from ahalogen atom, cyano, carbamoyl, C₁₋₆ alkyl-carbamoyl, C₁₋₆alkyl-carbonyloxy, C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkyl-carbamoyl, (5- or6-membered heterocyclic ring (e.g., 5- or 6-membered heterocyclic ringcontaining 1 to 3 heteroatom(s) selected from nitrogen, sulfur, oxygenatoms and the like in addition to carbon atoms))-C₁₋₆ alkyl-carbamoyl,C₁₋₆ alkylsulfonylamino, C₁₋₆ alkoxy-carbonyl, carboxy and the like],

[0425] (4) a C₃₋₆ cycloalkyl group (e.g., cyclohexyl),

[0426] (5) a C₆₋₁₄ aryl group (e.g., phenyl),

[0427] [this C₆₋₁₄ aryl group may have a substituent selected fromamino, carboxy, C₁₋₆ alkoxy-carbonyl, carbamoyl, mono- or di-C₁₋₆alkylcarbamoyl, formylamino, C₁₋₆ alkyl-carbonylamino which may have ahalogen atom or carboxy (e.g., acetylamino, propionylamino,trifluoroacetylamino, pivaloylamino), C₆₋₁₄ aryl-carbonylamino (e.g.,benzoylamino), C₁₋₆ alkoxy-carbonylamino (e.g., methoxycarbonylamino),ureido, mono- or di-C₁₋₆ alkylureido, C₁₋₆ alkylsulfonylamino (e.g.,methylsulfonylamino), (C₁₋₆ alkyl)(C₁₋₆ alkylsulfonyl)amino (e.g.,methyl(methylsulfonyl)amino), (C₁₋₆ alkyl)(C₁₋₆ alkyl-carbonyl)amino(e.g., methyl(acetyl)amino), C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkylamino (e.g.,2-ethoxycarbonyl-2-propylamino), C₇₋₁₅ aralkyloxy-carbonylamino (e.g.,benzyloxycarbonylamino), C₁₋₆ alkyl-carbonylamino-C₁₋₆alkyl-carbonylamino (e.g., acetylaminoacetylamino), C₁₋₆ alkylthio-C₁₋₆alkyl-carbonylamino (e.g., methylthioacetylamino), C₁₋₆alkyl-sulfinyl-C₁₋₆ alkyl-carbonylamino (e.g.,methylsulfinylacetylamino), C₁₋₆ alkyl-sulfonyl-C₁₋₆ alkyl-carbonylamino(e.g., methylsulfonylacetylamino), C₆₋₁₄ aryloxy-carbonylamino (e.g.,phenoxycarbonylamino), hydroxy-C₁₋₆ alkyl-carbamoyl (e.g.,hydroxymethylcarbamoyl, hydroxyethylcarbamoyl) and the like, and mayhave a substituent selected especially from amino, carboxy, C₁₋₆alkoxy-carbonyl, carbamoyl, mono- or di-C₁₋₆ alkylcarbamoyl,formylamino, C₁₋₆ alkyl-carbonylamino which may have a halogen atom orcarboxy (e.g., acetylamino, propionylamino, trifluoroacetylamino,pivaloylamino), C₁₋₆ alkoxy-carbonylamino (e.g., methoxycarbonylamino),ureido, C₁₋₆ alkylsulfonylamino (e.g., methylsulfonylamino), (C₁₋₆alkyl)(C₁₋₆ alkylsulfonyl)amino (e.g., methyl(methylsulfonyl)amino),(C₁₋₆ alkyl)(C₁₋₆ alkyl-carbonyl)amino (e.g., methyl(acetyl)amino), C₁₋₆alkoxy-carbonyl-C₁₋₆ alkylamino (e.g., 2-ethoxycarbonyl-2-propylamino),C₇₋₁₅ aralkyloxy-carbonylamino (e.g., benzyloxycarbonylamino) and thelike]

[0428] (6) a C₁₋₆ alkoxy group which may have a halogen atom or C₁₋₆alkoxy-C₆₋₁₄ aryl (e.g., methoxy, trifluoromethoxy, isopropoxy,2-(4-methoxyphenyl)ethoxy),

[0429] (7) a C₆₋₁₄ aryloxy group (e.g., phenoxy),

[0430] (8) a C₁₋₆ alkylthio group which may have a carbamoyl (e.g.,methylthio, carbamoylmethylthio),

[0431] (9) a C₁₋₆ alkylsulfinyl group which may have a carbamoyl (e.g.,methylsulfinyl, carbamoylmethylsulfinyl),

[0432] (10) a C₆₋₁₄ arylthio group (e.g., phenylthio),

[0433] (11) a hydroxy group,

[0434] (12) a 4- to 14-membered heterocyclic group containing 1 to 4heteroatom(s) selected from nitrogen, sulfur, oxygen atoms and, the likein addition to carbon atoms (e.g., pyrrolidinyl, piperidyl,isoindolinyl, furyl, thienyl, pyridyl, quinolyl, benzofuranyl,pyrimidinyl, tetrazolyl, imidazolidinyl, isothiazolidinyl,thiadiazolidinyl, azethinyl, etc.),

[0435] [this heterocyclic group may have a substituent selected fromoxo, carboxy-C₁₋₆ alkyl, C₁₋₆ alkyl-carbonyloxy-C₁₋₆ alkyl, C₁₋₆ alkyl,C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkyl, C₁₋₆ alkoxy-carbonyl, carbamoyl-C₁₋₆alkyl, C₁₋₆ alkyl-carbamoyl-C₁₋₆ alkyl, etc.],

[0436] (13) a carboxy group,

[0437] (14) a group represented by Formula: —CO-Hal (Hal is a halogenatom) (e.g., chloroformyl),

[0438] (15) a C₁₋₆ alkyl-carbonyl group (e.g., acetyl),

[0439] (16) a C₁6 alkyl-sulfonyl group (e.g., methylsulfonyl),

[0440] (17) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl),

[0441] (18) a sulfamoyl group

[0442] [this sulfamoyl group may have 1 or 2 substituent(s) selectedfrom C₁₋₆ alkyl, carbamoyl-C₁₋₆ alkyl, C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkyl,(5- to 7-membered heterocyclic group which may have an oxo groups (e.g.,5- to 7-membered heterocyclic group containing 1 to 3 heteroatom(s)selected from nitrogen, sulfur, oxygen atoms and the like in addition tocarbon atoms such as pyridyl, pyrrolidinyl hexahydroazepinyl))-C₁₋₆alkyl, C₁₋₆ alkyl-carbonylamino-C₆₋₁₄ aryl],

[0443] (19) a group represented by Formula: —NR^(a)R^(b)

[0444] [each of R^(a) and R^(b) is (i) a hydrogen atom, (ii) a C₁₋₆alkyl, (iii) a (5- or 6-membered heterocyclic ring (e.g., 5- or6-membered heterocyclic ring containing 1 to 3 heteroatom(s) selectedfrom nitrogen, sulfur, oxygen atoms and the like in addition to carbonatoms such as pyridyl))-C₁₋₆ alkyl, (iv) a C₁₋₆ alkoxy-carbonyl-C₁₋₆alkyl, (v) a di-C₁₋₆ alkylamino-methylene-sulfamoyl-C₁₋₆ alkyl, (vi) acarbamoyl-C₁₋₆ alkyl, (vii) a sulfamoyl-C₁₋₆ alkyl, (viii) a C₁₋₆alkyl-sulfonyl, (ix) a C₁₋₆ alkoxy-carbonyl, (x) a di-C₁₋₆alkoxy-carbonyl-C₂₋₆ alkenyl, (xi) a C₆₋₁₄ aryl, (xii) a 5- or6-membered heterocyclic ring (e.g., 5- or 6-membered heterocyclic ringcontaining 1 to 3 heteroatom(s) selected from nitrogen, sulfur, oxygenatoms and the like in addition to carbon atoms such as pyridyl), [this5- or 6-membered heterocyclic group may have a substituent selected fromamino, C₁₋₆ alkyl-carboxamido and C₁₋₆ alkyl-sulfonylamino and thelike], (xiii) an optionally halogenated C₁₋₆ alkyl-carbonyl, (xiv) aC₁₋₆ alkylthio-C₁₋₆ alkyl-carbonyl, (xv) a C₁₋₆ alkylsulfinyl-C₁₋₆alkyl-carbonyl, (xvi) a C₁₋₆ alkylsulfonyl-C₁₋₆ alkyl-carbonyl, (xvii)an amino-C₁₋₆ alkyl-carbonyl, (xviii) an optionally halogenated C₁₋₆alkyl-carbonyl-amino-C₁₋₆ alkyl-carbonyl, (xix) a C₆₋₁₄ aryl-carbonyl,(xx) a carboxy-C₆₋₁₄ aryl-carbonyl, (xxi) an optionally C₁₋₆alkyl-esterified phosphono-C₁₋₆ alkyl-C₆₋₁₄ aryl-carbonyl, (xxii) a (5-or 6-membered heterocyclic ring (e.g., 5- or 6-membered heterocyclicring containing 1 to 3 heteroatom(s) selected from nitrogen, sulfur,oxygen atoms and the like in addition to carbon atoms such aspyrrolidinyl, pyridyl) which may have a halogen atom, oxo or a C₁₋₆alkoxy-carbonyl)-carbonyl, (xxiii) a (5- or 6-membered heterocyclic ring(e.g., 5- or 6-membered heterocyclic ring containing 1 to 3heteroatom(s) selected from nitrogen, sulfur, oxygen atoms and the likein addition to carbon atoms such as pyridyl))-C₁₋₆ alkyl-carbonyl,(xxiv) a C₆₋₁₄ aryl-oxy-carbonyl, (xxv) a carboxy-C₁₋₆ alkyl, (xxvi) acarbamoyl, (xxvii) an optionally halogenated C₁₋₆ alkylcarbamoyl,(xxviii) a C₆₋₁₄ arylcarbamoyl which may have a C₁₋₆alkyl-carbonylamino, (xxix) a (5- or 6-membered heterocyclic ring (e.g.,5- or 6-membered heterocyclic ring containing 1 to 3 heteroatom(s)selected from nitrogen, sulfur, oxygen atoms and the like in addition tocarbon atoms such as pyridyl))-carbamoyl, (xxx) a C₂₋₆ alkenyl-carbonyl,(xxxi) a (5- or 6-membered heterocyclic ring (e.g., 5- or 6-memberedheterocyclic ring containing 1 to 3 heteroatom(s) selected fromnitrogen, sulfur, oxygen atoms and the like in addition to carbon atomssuch as pyrrolidinyl) which may have an oxo group)-amino-C₁₋₆alkyl-carbonyl, (xxxii) a (5- or 6-membered heterocyclic ring (e.g., 5-or 6-membered heterocyclic ring containing 1 to 3 heteroatom(s) selectedfrom nitrogen, sulfur, oxygen atoms and the like in addition to carbonatoms such as pyrrolidinyl) which may have an oxo group)(C₁₋₆ alkyl)amino-C₁₋₆ alkyl-carbonyl, (xxxiii) a (5- or 6-membered heterocyclicring (e.g., 5- or 6-membered heterocyclic ring-containing 1 to 3heteroatom(s) selected from nitrogen, sulfur, oxygen atoms and the likein addition to carbon atoms such as pyrrolidinyl) which may have an oxogroup) (C₁₋₆ alkylcarbonyl) amino-C₁₋₆ alkyl-carbonyl, (xxxiv) a C₁₋₆alkylthio-C₁₋₆ alkylcarbonyl (sulfur atom may be oxidized), (xxxv) anoptionally halogenated C₁₋₆ alkylsulfonyl, (xxxvi) a sulfamoyl, (xxxvii)a C₁₋₆ alkylsulfamoyl and the like],

[0445] (20) a group represented by Formula: —C(═O)NR^(c)R^(d)

[0446] [each of R^(c) and R^(d) is (i) a hydrogen atom, (ii) a C₁₋₆alkyl, (iii) a (5- or 6-membered heterocyclic ring (e.g., 5- or6-membered heterocyclic ring containing 1 to 3 heteroatom(s) selectedfrom nitrogen, sulfur, oxygen atoms and the like in addition to carbonatoms such as pyridyl, imidazolyl))-C₁₋₆ alkyl, (iv) a carboxy-C₁₋₆alkyl, (v) a C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkyl, (vi) a di-C₁₋₆alkylamino-C₁₋₆ alkyl, (vii) a carbamoyl-C₁₋₆ alkyl, (viii) a C₁₋₆alkylcarbamoyl-C₁₋₆ alkyl, (ix) a (5- or 6-membered heterocyclic ring(e.g., 5- or 6-membered heterocyclic ring containing 1 to 3heteroatom(s) selected from nitrogen, sulfur, oxygen atoms and the likein addition to carbon atoms such as pyridyl))-C₁₋₆ alkylcarbamoyl-C₁₋₆alkyl, (x) a (5- or 6-membered heterocyclic ring (e.g., 5- or 6-memberedheterocyclic ring containing 1 to 3 heteroatom(s) selected fromnitrogen, sulfur, oxygen atoms and the like in addition to carbon atomssuch as pyridyl))-amino-C₁₋₆ alkyl, (xi) a sulfamoyl-C₆₋₁₄ aryl-C₁₋₆alkyl, (xii) a C₆₋₁₄ aryl which may have a C₁₋₆ alkoxy, (xiii) anoptionally C₁₋₆ alkyl-esterified phosphono-C₁₋₆ alkyl-C₆₋₁₄ aryl, (xiv)a 4- to 10-membered heterocyclic group (e.g., 4- to 10-memberedheterocyclic ring containing 1 to 3 heteroatom(s) selected fromnitrogen, sulfur, oxygen atoms and the like in addition to carbon atomssuch as azethinyl, pyrrolidinyl, piperidinyl, hexahydroazepinyl,pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,1-azabicyclo[2.2.2]octo-3-yl) [this 4- to 10-membered heterocyclic groupmay have 1 to 2 substituent(s) selected from a halogen atom, C₁₋₆ alkyland oxo], (xv) a C₆₋₁₄ aryl-carbamoyl-C₁₋₆ alkyl, (xvi) a hydroxy-C₁₋₆alkyl or (xvii) a (5- or 6-membered heterocyclic ring (e.g., 5- or6-membered heterocyclic ring containing 1 to 3 heteroatom(s) selectedfrom nitrogen, sulfur, oxygen atoms and the like in addition to carbonatoms such as pyrrolidinyl, pyridyl) which may have a oxogroup)-carbamoyl-C₁₋₆ alkyl; and R^(c) is preferably a hydrogen atom],

[0447] (21) a cyano group,

[0448] (22) a mono- or di-C₁₋₆ alkylcarbamoylthio group (e.g.,dimethylcarbamoylthio),

[0449] (23) a mono- or di-C₁₋₆ alkylthiocarbamoyloxy group (e.g.,dimethylthiocarbamoyloxy).

[0450] A “heterocyclic group” as a preferred group R¹ is preferablypyridyl, thienyl, furyl, imidazolyl, thiazolyl, quinolyl,1,2-dihydropyridyl, dihydrobenzofuranyl, benzodioxolyl, benzothiazolyl,piperidyl, piperazinyl and the like, with pyridyl and 1,2-dihydropyridylbeing preferred especially.

[0451] Preferred substituents on this “heterocyclic group” may forexample be 1 to 5, preferably 1 to 3 groups selected from:

[0452] (1) a halogen atom,

[0453] (2) a C₁₋₆ alkyl group (e.g., methyl, ethyl, etc.) [this alkylmay have a substituent selected from carboxy, C₁₋₆ alkoxy, C₁₋₆alkoxy-carbonyl, mono-C₁₋₆ alkyl-amino, di-C₁₋₆ alkyl-amino, carbamoyl,C₁₋₆ alkyl-carbamoyl which may have a hydroxy, 4- to 10-memberedheterocyclic group (e.g., 4- to 10-membered heterocyclic groupcontaining 1 to 3 heteroatom(s) selected from nitrogen, sulfur, oxygenatoms and the like in addition to carbon atoms such as pyridyl,quinolyl, etc.) which may have oxo, (4- to 10-membered heterocyclicgroup (e.g., 4- to 10-membered heterocyclic group containing 1 to 3heteroatom(s) selected from nitrogen, sulfur, oxygen atoms and the likein addition to carbon atoms such as pyridyl, quinolyl))-carbamoyl,carbamoyl-C₁₋₆ alkyl-carbamoyl, etc.],

[0454] (3) a C₁₋₆ alkoxy group (e.g., methoxy),

[0455] (4) a C₆₋₁₄ aryl group (e.g., phenyl),

[0456] (5) a C₇₋₁₆ aralkyl group (e.g., benzyl)

[0457] [this C₇₋₁₆ aralkyl group may have a substituent selected fromcarboxy, C₁₋₆ alkoxy-carbonyl, carbamoyl, C₁₋₆ alkyl-carbamoyl which mayhave a hydroxy, (4- to 10-membered heterocyclic group (e.g., 4- to10-membered heterocyclic group containing 1 to 3 heteroatom(s) selectedfrom nitrogen, sulfur, oxygen atoms and the like in addition to carbonatoms such as pyridyl))-carbamoyl and the like],

[0458] (6) a 4- to 10-membered heterocyclic group (e.g., 4- to10-membered heterocyclic group containing 1 to 3 heteroatom(s) selectedfrom nitrogen, sulfur, oxygen atoms and the like in addition to carbonatoms such as pyridyl, quinolyl, isoquinolyl, etc.)

[0459] [this 4- to 10-membered heterocyclic group may have a substituentselected from a C₁₋₆ alkyl, C₁₋₆ alkoxy-carbonyl, carbamoyl, oxo, 4- to10-membered heterocyclic group (e.g., 4- to 10-membered heterocyclicgroup containing 1 to 3 heteroatom(s) selected from nitrogen, sulfur,oxygen atoms and the like in addition to carbon atoms such as pyridyl,etc.)],

[0460] (7) an oxo group,

[0461] (8) an oxide group.

[0462] A heterocyclic group whose R¹ has an oxide group is preferablyN-oxidized pyridyl and the like.

[0463] An “alicyclic hydrocarbon group” as a preferred group R¹ is aC₃₋₆ cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl, etc., with cyclopentyl and cyclohexyl being preferredespecially.

[0464] This “alicyclic hydrocarbon group” may have a substituent similarto a substituent which may be possessed by a hydrocarbon grouprepresented by R¹ described above.

[0465] Each of an “optionally substituted aromatic hydrocarbon group”and “optionally substituted heterocyclic group” as a preferred group R¹is preferably a group represented by Formula:

[0466] wherein each symbol is defined as described above.

[0467] An “optionally substituted hydrocarbon group” represented byR^(1b) is a group similar to an “optionally substituted hydrocarbongroup” exemplified as a substituent on Ring A. Among such groups, thoseemployed preferably are:

[0468] (1) a C₁₋₆ alkyl group (e.g., methyl, isopropyl, tert-butyl,etc.)

[0469] [this C₁₋₆ alkyl group may have a substituent selected from ahalogen atom, cyano, hydroxy, C₁₋₆ alkoxy-carbonyl, di-C₁₋₆ alkylamino,optionally halogenated C₁₋₆ alkyl-carbonyl-amino, carboxy, carbamoyl,C₁₋₆ alkyl-carbamoyl, C₁₋₆ alkyl-carbonyloxy, C₁₋₆ alkoxy-carbonyl-C₁₋₆alkyl-carbamoyl, (5- or 6-membered heterocyclic ring (e.g., 5- or6-membered heterocyclic ring containing 1 to 3 heteroatom(s) selectedfrom nitrogen, sulfur, oxygen atoms and the like in addition to carbonatoms such as pyridyl, imidazolyl))-C₁₋₆ alkyl-carbamoyl, C₁₋₆alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonylamino, (5- or6-membered heterocyclic ring (e.g., 5- or 6-membered heterocyclic ringcontaining 1 to 3 heteroatom(s) selected from nitrogen, sulfur, oxygenatoms and the like in addition to carbon atoms such as pyridyl))-C₁₋₆alkylcarbamoyl, (5- or 6-membered heterocyclic ring (e.g., 5- or6-membered heterocyclic ring containing 1 to 3 heteroatom(s) selectedfrom nitrogen, sulfur, oxygen atoms and the like in addition to carbonatoms such as pyridyl))-amino, sulfamoyl-C₆₋₁₄ aryl, carboxy-C₆₋₁₄ aryl,C₁₋₆ alkoxy-carbonyl-C₆₋₁₄ aryl, carbamoyl-C₆₋₁₄ aryl, C₁₋₆alkyl-carbamoyl-C₆₋₁₄ aryl which may have a hydroxy, (4- to 10-memberedheterocyclic ring (e.g. 4- to 10-membered heterocyclic ring containing 1to 3 heteroatom(s) selected from nitrogen, sulfur, oxygen atoms and thelike in addition to carbon atoms such as pyridyl))-carbamoyl-C₆₋₁₄aryl],

[0470] (2) a C₃₋₆ cycloalkyl group (e.g., cyclohexyl),

[0471] (3) a C₆₋₁₄ aryl group (e.g., phenyl)

[0472] [this C₆₋₁₄ aryl group may have a substituent selected from C₁₋₆alkoxy (e.g., methoxy), amino, carboxy, optionally halogenated C₁₋₆alkyl-carbonylamino (e.g., acetylamino, trifluoroacetylamino), C₁₋₆alkoxy-carbonylamino (e.g., methoxycarbonylamino), formylamino, ureido,C₁₋₆ alkylsulfonylamino (e.g., methylsufonylamino), (C₁₋₆ alkyl)(C₁₋₆alkylsulfonyl) amino (e.g., methyl(methylsulfonyl)amino), C₁₋₆alkoxy-carbonyl-C₁₋₆ alkylamino (e.g., 2-ethoxycarbonyl-2-propylamino,etc.), optionally C₁₋₆ alkyl-esterified phosphono-C₁₋₆ alkyl, mono- ordi-C₁₋₆ alkyl-carbamoyl, C₇₋₁₆ aralkyloxy-carbonylamino (e.g.,benzyloxycarbonylamino, etc.)].

[0473] An “optionally substituted heterocyclic group” represented byR^(1b) is one similar to an “optionally substituted heterocyclic group”exemplified as a substituent on Ring A. Among such groups, thoseemployed preferably are a 5- to 14-membered heterocyclic ring containing1 to 4 heteroatom(s) selected from nitrogen, sulfur, oxygen atoms andthe like in addition to carbon atoms (e.g., azethinyl, pyrrolidinyl,piperidinyl, isothiazolidinyl, thiadiazolidinyl, hexahydroazepinyl,furyl, thienyl, pyridyl, quinolyl, isoquinolyl, benzofuranyl,pyrimidinyl, tetrazolyl, imidazolinyl, pyrazinyl, pyridazinyl and thelike) which may be substituted by 1 or 2 substituent(s) selected from ahalogen atom, C₁₋₆ alkyl, carboxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-carbonyl-C₁₋₆alkyl, C₁₋₆ alkoxy-carbonyl, carbamoyl, oxo, 4- to 10-memberedheterocyclic group (4- to 10-membered heterocyclic group containing 1 to3 heteroatom(s) selected from nitrogen, sulfur, oxygen atoms and thelike in addition to carbon atoms such as pyridyl, etc.), (4) C₂₋₆alkenyl group and the like.

[0474] An aromatic hydrocarbon ring represented by Ring D may forexample be a monocyclic or fused polycyclic aromatic hydrocarbon ring(C₆₋₁₄ aryl ring) having 6 to 14 carbon atoms. Such a C₆₋₁₄ aryl ringmay for example be a benzene ring, naphthalene ring, anthryl ring,phenanthryl ring, with a benzene ring and naphthalene ring beingpreferred and a benzene ring being especially preferred.

[0475] Any of these aromatic hydrocarbon groups may have 1 to 5,preferably 1 to 3 substituent(s) selected from Substituent Group Adescribed above.

[0476] A heterocyclic ring represented by Ring D may for example be a 5-to 14-membered heterocyclic ring containing 1 to 4 (preferably 1 to 3)heteroatom(s) selected from nitrogen, 10 sulfur and oxygen atoms inaddition to carbon atoms, typically, (a) a 5- to 14-membered aromaticheterocyclic ring, (b) a 5- to 14-membered aliphatic heterocyclic ring,(c) a bicyclic or tricyclic fused ring of 5- to 14-membered aromaticheterocyclic ring(s) with benzene ring(s) and the like.

[0477] Said 5- to 14-membered aromatic heterocyclic ring may for examplebe a 5- to 14-membered aromatic heterocyclic ring containing 1 to 4(preferably 1 to 3) heteroatom(s) selected from nitrogen, sulfur andoxygen atoms in addition to carbon atoms, and those exemplifiedtypically are thiophene, furan, indolizine, pyrrole, imidazole,triazole, thiazole, oxazole, pyrazole, pyridine, pyridine N-oxide,pyrazine, pyrimidine, pyridazine, purine, 4H-quinolizine, naphthyridine,isothiazole, isoxazole, furazane and the like. Among those listed above,pyridine, thiophene and furan are employed preferably.

[0478] Said 5- to 14-membered aliphatic heterocyclic ring may forexample be a 5- to 14-membered aliphatic heterocyclic ring containing 1to 4 (preferably 1 to 3) heteroatom(s) selected from nitrogen, sulfurand oxygen atoms in addition to carbon atoms, and those exemplifiedtypically are pyrrolidine, piperidine, piperazine, morpholine,thiomorpholine, 1,2-dihydropyridine, imidazolidine and the like.

[0479] Said a bicyclic or tricyclic fused ring of 5- to 14-memberedaromatic heterocyclic ring(s) with benzene-rings may for example be abicyclic or tricyclic fused ring of 5- to 14-membered heterocyclic ringcontaining 1 to 4 (preferably 1 to 3) heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms in addition to carbon atoms withbenzene ring(s), and those exemplified typically are benzo[b]thiophene,benzofuran, 1H-benzimidazole, benzoxazole, benzothiazole,1,2-benzisothiazole, naphtho[2,3-b]thiophene, thianthrene, xanthene,phenoxathiin, indole, isoindole, 1H-indazole, isoquinoline, quinoline,phthalazine, quinoxaline, quinazoline, cinnoline, carbazole,β-carboline, phenanthridine, acridine, phenazine, phenothiazine,phenoxazine, isochroman, dihydrobenzofuran and the like.

[0480] Among those listed above, a preferred heterocyclic ringrepresented by Ring D is pyridine, thiophene, furan, imidazole,thiazole, quinoline, pyridine N-oxide, 1,2-dihydropyridine,dihydrobenzofuran, benzodioxole, benzothiazole, piperidine, piperazineand the like, with pyridine, 1,2-dihydropyridine being especiallypreferred.

[0481] Any of these heterocyclic rings may have 1 to 5, preferably 1 to3 substituent(s) selected from Substituent Group A described above.

[0482] An “optionally oxidized sulfur atom” represented by E is S, SO,SO₂ and the like.

[0483] An optionally substituted nitrogen atom represented by E may forexample be a nitrogen atom which may have 1 to 2 group(s) selected from(i) a hydrogen atom, (ii) an optionally substituted hydrocarbon group,(iii) an acyl group and the like.

[0484] Said “optionally substituted hydrocarbon group” may be onesimilar to an “optionally substituted hydrocarbon group”0 exemplified asa substituent on Ring A.

[0485] Said “acyl group” may be one similar to an “acyl group”exemplified as a substituent on Ring A, and this acyl group may furtherhave 1 to 5, preferably 1 to 3 substituent(s) selected from SubstituentGroup A described above.

[0486] In a group represented by Formula: —CS—O—, —CO—O—, —S—CO—,—(CH₂)_(k)—CO—, —NR^(1c) CO—(CH₂)_(m)—, —NR^(1c)—SO₂—(CH₂)_(m)—,—SO₂—NR^(1c)—(CH₂)_(m)—, —O—CS—NR^(1c)—(CH₂)_(m)—,—NR^(1c)—CO—NR^(1c)—(CH₂)_(m)—, —NR^(1c)—CO—CH₂—(CH₂)_(m)—NR^(1c)—wherein R^(1c) is a hydrogen atom, optionally substituted alkyl group oracyl group, k is 0 or 1, m is an integer of 0 to 3 which is representedby E, an alkyl group represented by R^(1c) may for example be a C₁₋₆alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl and the like.

[0487] An alkyl group represented by R^(1c) may have 1 to 5, preferably1 to 3 substituent(s) selected from Substituent Group A described above.

[0488] An acyl group represented by R^(1c) may for example be onesimilar to an “acyl group” exemplified as a substituent on Ring A, andthis acyl group may further have 1 to 5, preferably 1 to 3substituent(s) selected from Substituent Group A described above.

[0489] k is 0 or 1, especially 0.

[0490] m is an integer of 0 to 3, especially 0 to 1.

[0491] Among those listed above, those preferred as E are:

[0492] (i) a bond, (ii) methylene, (iii) 0, (iv) S, (v) SO, (vi) SO₂,(vii) —NH—, (viii) —N(C₁₋₆ alkyl)-(e.g., —N(methyl)-, etc.), (ix)—N(C₁₋₆ alkyl-carbonyl)-(e.g., —N(acetyl), etc.), (x) —N(C₁₋₆alkoxy-carbonyl)-(e.g., —N(ethoxycarbonyl), etc.), (xi) —N(C₁₋₆alkyl-sulfonyl)-(e.g., —N(methylsulfonyl)-, etc.),

[0493] (xii)—CO—O—, (xiii)—S—CO—, (xiv) a group represented by Formula:—(CH₂)_(k)—CO wherein k is 0 or 1, (xv) —NR^(f)—CO—(CH₂)_(m1)—whereinR^(f) is a hydrogen atom, C₁₋₆ alkoxy-carbonyl (e.g., methoxycarbonyl)or C₁₋₆ alkyl group which.may be substituted by a heterocyclic groupcontaining 1 to 3 heteroatom(s) selected from nitrogen, oxygen, sulfuratoms and the like in addition to carbon atoms (e.g. pyridyl), and m1 isan integer of 0 to 3,

[0494] (xvi) a group represented by Formula —NR⁹—SO₂—(CH₂)_(m2)— whereinR^(g) is a hydrogen atom or C₁₋₆ alkyl-sulfonyl group (e.g.,methylsulfonyl) and m2 is 0,

[0495] (xvii) a group represented by —SO₂—NR^(h)—(CH₂)_(m3)— whereinR^(h) is a hydrogen atom or C₁₋₆ alkyl group (e.g., methyl) and m3 is 0or 1,

[0496] (xviii) a group represented by —O—CS—NR¹—(CH₂)_(m4)— wherein R¹is a hydrogen atom or C₁₋₆ alkyl group (e.g., methyl) and m4 is 0 or 1,

[0497] (xix) a group represented by —NR^(j)—CO—NR_(k)(CH₂)_(m5)— whereinR^(j) is a hydrogen atom or C₁₋₆ alkyl group (e.g., methyl), R^(k) is ahydrogen atom or C₁₋₆ alkyl group (e.g., methyl) and m5 is 0 or 1,

[0498] (xx) a group represented by —NR^(L)—CO—CH₂—(CH₂)_(m6)—NR^(m)—wherein R^(L) is a hydrogen atom or C₁₋₆ alkyl group (e.g., methyl),R^(m) is a hydrogen atom or C₁₋₆ alkyl group (e.g., methyl) and m6 is 0or 1.

[0499] Each of an “optionally substituted aromatic hydrocarbon group”and “optionally substituted heterocyclic group” exemplified as apreferred R¹ may also be a group represented by Formula:

[0500] wherein each symbol is defined as described above.

[0501] A halogen atom represented by Hal may for example be a fluorineatom, chlorine atom, bromine atom and iodine atom, with a chlorine atombeing preferred.

[0502] As Ring D, one similar to those described above can be employed.

[0503] In a group represented by Formula : —L—R^(1a) wherein each symbolis defined as described above exemplified as a preferred group R¹, an“optionally substituted nitrogen atom” represented by L may be onesimilar to an “optionally substituted nitrogen atom ” represented by E.L is preferably methylene, carbonyl, —NH—and the like.

[0504] An aromatic group represented by R^(1a) may for example be:

[0505] <1> a monocyclic or fused polycyclic aromatic hydrocarbon group,typically, a 6- to 14-membered monocyclic or fused polycyclic aromatichydrocarbon group such as a C₆₋₁₄ aryl group such as phenyl, 1-naphthyl,2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl,2-phenanthryl, 3-phenanthryl, 4-phenanthryl or 9-phenanthryl,(preferably phenyl, 1-naphthyl or 2-naphthyl, especially, phenyl),

[0506] <2> a 4- to 14-membered aromatic heterocyclic group containingone or more (for example 1 to 4, preferably 1 to 3) heteroatom(s) of 1or 2 kind(s) selected from nitrogen, sulfur and oxygen atoms in additionto carbon atoms.

[0507] Such a 4- to 14-membered aromatic heterocyclic group may forexample be a monocyclic heterocyclic group (preferably 5- to 8-memberedgroup) containing one or more (for example 1 to 4, preferably 1 to 3)heteroatom(s) of 1 or 2 kind(s) selected from nitrogen, sulfur andoxygen atoms in addition to carbon atoms or a fused aromaticheterocyclic group thereof, typically, an aromatic heterocyclic ringsuch as thiophene, benzo[b]thiophene, benzofuran, 1H-benzimidazole,benzoxazole, benzothiazole, 1,2-benzisothiazole,naphtho[2,3-b]thiophene, thianthrene, furan, indolizine, xanthene,phenoxathiin, pyrrole, imidazole, triazole, thiazole, oxazole, pyrazole,pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole,1H-indazole, purine, 4H-quinolizine, isoquinoline, quinoline,phthalazine naphthyridine, quinoxaline, quinazoline, cinnoline,carbazole, β-carboline, phenanthridine, acridine, phenazine,isothiazole, phenothiazine, isoxazole, furazane, phenoxazine, isochromanand the like (preferably, pyridine, thiophene or furan, more preferablypyridine) or a fused ring group of one or more (preferably 1 or 2, morepreferably 1) of these rings (preferably monocyclic heterocyclic ring)with aromatic rings (for example, aromatic hydrocarbon groups describedabove, preferably benzene rings).

[0508] Substituents on said aromatic group are 1 to 5, preferably 1 to 3substituent(s) selected from Substituent Group A described above.

[0509] An aromatic group which may have a substituent represented byR^(1a) is preferably a C₆₋₁₄ aryl group (e.g., phenyl) which may have 1to 5 substituent(s) such as a C₁₋₆ alkyl and C₁₋₆ alkoxy, etc.

[0510] An “optionally substituted hydroxy group” represented by R^(1a)is one similar to an “optionally substituted hydroxy group” exemplifiedas a substituent on Ring A, with a hydroxy group which may have a C₁₋₆alkyl group (e.g., methyl) being preferred.

[0511] An “optionally substituted amino group” represented by R^(1a) isone similar to an “optionally substituted amino group” exemplified as asubstituent on Ring A.

[0512] A preferred “optionally substituted amino group” represented byR^(1a) may for example be an amino group which may have 1 or 2 group(s)such as an optionally substituted alkyl group or optionally substitutedaryl group, especially <1> a C₁₋₆ alkyl-amino group which may besubstituted by a 4- to 10-membered heterocyclic group (4- to 10-memberedheterocyclic group containing 1 to 3 heteroatom(s) selected fromnitrogen, oxygen, sulfur atoms and the like in addition to carbon atoms,e.g., pyridyl), <2> a C₆₋₁₄ aryl-amino group, <3> a 4- to 10-memberedheterocyclic group (4- to 10-membered heterocyclic group containing 1 to3 heteroatom(s) selected from nitrogen, oxygen, sulfur atoms and thelike in addition to carbon atoms, e.g., pyridyl)-amino group and thelike.

[0513] An “optionally substituted hydrocarbon group” represented by R²and R³ is one similar to an “optionally substituted hydrocarbon group”exemplified as a substituent on Ring A.

[0514] Such an “optionally substituted hydrocarbon group” may forexample be a hydrocarbon group (especially C₁₋₆ alkyl group) which maybe substituted by:

[0515] <1> a halogen atom,

[0516] <2> an optionally substituted hydroxy group (for example, ahydroxy group which may be substituted by a substituent selected from aC₁₋₆ alkyl, C₁₋₆ alkyl-carbonyl, C₁₋₆ alkylsulfonyl and C₇₋₁₆ aralkyl,etc.),

[0517] <3> an optionally substituted amino group (for example, an aminogroup which may be substituted by 1 to 2 C₁₋₆ alkyl, C₁₋₆ alkyl-carbonyland C₆₋₁₄ aryl-carbonyl),

[0518] <4> an optionally substituted 4- to 10-membered heterocyclicgroup (for example, a 4- to 10-membered heterocyclic group containing 1to 3 heteroatom(s) selected from nitrogen, oxygen, sulfur atoms and thelike in addition to carbon atoms which may have an oxo group (e.g.,phthalimido, imidazolinyl, piperidinyl, pyrrolidinyl)),

[0519] <5> an optionally substituted thio group (for example, a thiogroup which may be substituted by C₁₋₆ alkyl, etc.),

[0520] <6> a C₁₋₆ alkyl-sulfinyl group,

[0521] <7> a C₁₋₆ alkyl-sulfonyl group.

[0522] Among those listed above, one employed preferably is a C₁₋₆ alkylgroup which may be substituted by <1> a halogen atom (especially,bromine atom), <2> a hydroxy, <3> a C₁₋₆ alkyl-carbonyloxy (e.g.,acetoxy), <4> an amino, <5> a 4- to 10-membered heterocyclic group (4-to 10-membered heterocyclic group containing 1 to 3 heteroatom(s)selected from nitrogen, oxygen, sulfur atoms and the like in addition tocarbon atoms (e.g., phthalimido, imidazolinyl, piperidinyl,pyrrolidinyl)) which may have oxo group and the like, and one employedmore preferably is a C₁₋₆ alkyl group (e.g., methyl, ethyl) which may behalogenated by a halogen atom (especially, bromine atom), with a methylgroup being preferred especially.

[0523] An “acyl group” represented by R² and R³ is one similar to an“acyl group” exemplified as a substituent on Ring A, with a C₁₋₆alkoxy-carbonyl group being preferred and a methoxycarbonyl group beingmore preferred.

[0524] A 3- to 8-membered ring formed by R² and R³ together with theadjacent carbon atom may for example be a 3- to 8-membered homocyclic orheterocyclic ring.

[0525] A 3- to 8-membered homocyclic ring formed by R² and R³ togetherwith the adjacent carbon atom may for example be a 3- to 8-memberedcyclic hydrocarbon consisting of carbon atoms, and typically a C₃₋₈cycloalkane (for example, cyclobutane, cyclopentane, cyclohexane,cycloheptane, cyclooctane), C₃₋₈ cycloalkene (for example, cyclobutene,cyclopentene, cyclohexene, cycloheptene, cyclooctene) may beexemplified. Among those listed above, a C₃₋₈ cycloalkane is preferred,with a 5- or 6-membered homocyclic ring such as cyclopentane andcyclohexane (especially, cyclohexane) being particularly preferred.

[0526] A 3- to 8-membered heterocyclic ring formed by R² and R³ togetherwith the adjacent carbon atom may for example be a 5- to 8-memberedaliphatic heterocyclic ring containing one or more (for example 1 to 4,preferably 1 to 3) heteroatom(s) of 1 or 2 kind(s) selected fromnitrogen, sulfur and oxygen atoms in addition to carbon atoms.

[0527] More specifically, a 5- to 8-membered aliphatic heterocyclic ringcontaining 1 to 3 heteroatom(s) selected from nitrogen, oxygen andsulfur atoms in addition to carbon atoms and a nitrogen atom such aspiperidine, piperazine, morpholine, thiomorpholine, pyrrolidine,imidazolidine ring and the like.

[0528] Such a 3- to 8-membered homocyclic or heterocyclic ring formed byR² and R³ together with the adjacent carbon atom may have 1 to 5,preferably 1 to 3 substituent(s) similar to the substituents which maybe possessed by a heterocyclic ring represented by R¹ described above.Such substituents are preferably 1 to 3 group(s) selected from a C₁₋₆alkyl, C₆₋₁₄ aryl, C₇₋₁₆ aralkyl, amino, mono-C₁₋₆ alkylamino,mono-C₆₋₁₄ arylamino, di-C₁₋₆ alkylamino, di-C₆₋₁₄ arylamino, 4- to 10-membered (e.g., 4- to 10-membered (preferably 5- or 6-membered)heterocyclic ring containing 1 to 3 heteroatom(s) selected fromnitrogen, oxygen and sulfur atoms in addition to carbon atoms) and thelike.

[0529] Among those listed above, each of R² and R³ is preferably a C₁₋₆alkyl group, C₁₋₆ alkoxy-carbonyl group each of which may be a halogenatom, with a methyl group and methoxycarbonyl group being preferred.

[0530] It is also preferred that R² and R³ are taken together with theadjacent carbon atom to form a 5- or 6-membered homocyclic ring such asa C₃₋₈ cycloalkane, preferably cyclopentane and cyclohexane (especially,cyclohexane).

[0531] An “optionally substituted hydrocarbon group” represented by R⁴may be one similar to an “optionally substituted hydrocarbon group”exemplified as a substituent on Ring A.

[0532] A hydrocarbon group represented by R⁴ is preferably a C₁₋₆ alkylgroup (e.g., methyl, ethyl, propyl, isopropyl, etc.), C₂₋₆ alkenyl group(e.g., 2-methyl-2-propenyl, etc.), with a C₁₋₃ alkyl group such asmethyl and isopropyl being preferred especially.

[0533] A substituent on said hydrocarbon group is preferably (1) ahalogen atom (for example, fluorine, chlorine, bromine, iodine), (2) acyano group, (3) a lower alkoxy group (e.g., methoxy, ethoxy), (4) ahydroxy group, (5) an amino group, (6) a mono-lower alkylamino group(e.g., mono-C₁₋₆ alkylamino group such as methylamino, ethylamino), (7)a di-lower alkylamino group (e.g., di-C₁₋₆ alkylamino group such asdimethylamino and diethylamino, etc.), (8) a 4- to 10-memberedheterocyclic ring containing 1 to 3 heteroatom(s) selected fromnitrogen, oxygen and sulfur atoms in addition to carbon atoms which mayhave an oxo group (e.g., piperidino, 2-isoindolinyl, etc.), (9) a C₆₋₁₄arylthio (e.g., phenylthio), (10) an ureido, (11) a carboxy, (12) acarbamoyl, (13) a C₁₋₆ alkoxy-carbonyl (e.g., methoxycarbonyl,ethoxycarbonyl, etc.), (14) a mono-C₁₋₆ alkyl-carbamoyl (e.g.,methylcarbamoyl, ethylcarbamoyl, etc.), (15) a formylamino and (16) aC₁₋₆ alkyl-carboxamido (e.g., acetamido, propionamido).

[0534] An “acyl group” represented by R⁴ may be one similar to an “acylgroup” exemplified as a substituent on Ring A, and is typically (1)formyl (2) a C₁₋₆ alkyl-carbonyl group (e.g., acetyl, propionyl, etc.),(3) a C₆₋₁₄ aryl-carbonyl group (e.g., benzoyl, etc.), (4) a C₇₋₁₆aralkyl-carbonyl group (e.g., phenylacetyl, etc.) (5) a C₁₋₆alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl), (6) acarbamoyl group, (7) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g.,methylcarbamoyl, dimethylcarbamoyl, etc.), (8) a mono- or di-C₁₋₆alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl,dimethylthiocarbamoyl, etc.), (9) a C₁₋₆ alkyl-sulfonyl group (e.g.,methylsulfonyl, etc.), (10) a C₁₋₆ alkyl-sulfinyl group (e.g.,methylsulfinyl, etc.) and the like, with formyl being preferred.

[0535] An “optionally substituted hydroxy group” represented by R⁴ mayfor example be a group represented by Formula: —OR⁴′ (R⁴′ is a hydrogenatom, optionally substituted hydrocarbon group or acyl group).

[0536] A hydrocarbon group which may have a substituent represented byR⁴′ may for example be one similar to an “optionally substitutedhydrocarbon group” exemplified as a substituent on Ring A, with C₁₋₆alkyl being preferred.

[0537] An acyl group represented by R⁴′ may for example be one similarto an “acyl group” exemplified as a substituent on Ring A, with C₁₋₆alkyl-carbonyl being preferred.

[0538] R⁴ is preferably a hydrogen atom, cyano group, C₁₋₆ alkyl groupwhich may be substituted by a cyano, formyl and the like, with ahydrogen atom being preferred especially.

[0539] An “optionally substituted hydrocarbon group” represented by R⁵is one similar to an “optionally substituted hydrocarbon group”exemplified as a substituent on Ring A.

[0540] A hydrocarbon group represented by R⁵ is preferably a C₁₋₆ alkylgroup (e.g., methyl, ethyl, etc.), C₂₋₆ alkenyl group (e.g., allyl,2-methyl-2-propenyl, etc.), a C₂₋₆ alkynyl group (e.g., propargyl,etc.), a C₃₋₆ cycloalkyl group (e.g., cyclopentyl, etc.), a C₇₋₁₆aralkyl group (e.g., benzyl, 3-phenylpropyl, 5-phenylpentyl, etc.) andthe like, with a C₁₋₆ alkyl group (especially, methyl) beingparticularly preferred.

[0541] A substituent on said hydrocarbon group is preferably (1) ahalogen atom (for example, fluorine, chlorine, bromine, iodine), (2) ahydroxy group, (3) an amino group, (4) a carboxy, (5) a carbamoyl, (6) aC₁₋₆ alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, etc.), (7)a mono-C₁₋₆ alkyl-carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl,etc.), (8) a di-C₁₋₆ alkyl-carbamoyl (e.g., dimethylcarbamoyl,diethylcarbamoyl, etc.), (9) a 4- to 10-membered heterocyclic groupcontaining 1 to 3 heteroatom(s) selected from nitrogen, sulfur, oxygenatoms and the like in addition to carbon atoms (e.g., pyridyl,isoindolinyl) which may have an oxo, (11) a C₆₋₁₄ aryl group (e.g.,phenyl, etc.) and the like.

[0542] An “acyl group” represented by R⁵ is one similar to an “acylgroup” exemplified as a substituent on Ring A, and this acyl group mayfurther have 1 to 5, preferably 1 to 3 substituent(s) selected fromSubstituent Group A described above. Those preferred especially are (1)formyl (2) a C₁₋₆ alkyl-carbonyl group (e.g., acetyl, propionyl, etc.),(3) a C₆₋₁₄ aryl-carbonyl group (e.g., benzoyl, etc.), (4) a C₇₋₁₆aralkyl-carbonyl group (e.g., phenylacetyl, etc.) (5) a C₁₋₆alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, etc.), (6)a carbamoyl group, (7) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g.,methylcarbamoyl, dimethylcarbamoyl, etc.), (8) a mono- or di-C₁₋₆alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl,dimethylthiocarbamoyl, etc.), (9) a C₁₋₆ alkyl-sulfonyl group (e.g.-,methylsulfonyl, etc.), (10) a C₁₋₆ alkyl-sulfinyl group (e.g.,methylsulfinyl, etc.) and the like.

[0543] An “optionally substituted heterocyclic group” represented by R⁵is one similar to an “optionally substituted heterocyclic group”exemplified as a substituent on Ring A.

[0544] A heterocyclic group represented by R⁵ is preferably a 4- to10-membered aromatic heterocyclic ring containing 1 to 4 heteroatom(s)selected from nitrogen, sulfur, oxygen atoms and the like in addition tocarbon atoms (e.g., tetrazolyl, etc.), etc.

[0545] A substituent on said heterocyclic group is preferably a C₆₋₁₄aryl group (e.g., phenyl, etc.) and the like.

[0546] A halogen atom represented by R⁵ is a fluorine atom, chlorineatom, bromine atom and iodine atom, with a chlorine atom beingpreferred.

[0547] Depending on X⁵, R⁵ is preferably any of those described below:

[0548] [X═oxygen atom]

[0549] (i) a hydrogen atom,

[0550] (ii) a C₁₋₆ alkyl group (e.g., methyl, ethyl, isopropyl, butyl,etc.)

[0551] [this C₁₋₆ alkyl group may have a substituent selected from (1) ahalogen atom, (2) a hydroxy group, (3) an amino group, (4) a carboxy,(5) a carbamoyl, (6) a C₁₋₆ alkoxy-carbonyl, (7) a mono-C₁₋₆alkyl-carbamoyl, (8) a di-C₁₋₆ alkyl-carbamoyl, (9) 4- to 10-memberedaromatic heterocyclic group containing 1 to 3 heteroatom(s) selectedfrom nitrogen, sulfur, oxygen atoms and the like in addition to carbonatoms (e.g., pyridyl, 2-isoindolinyl, etc.)],

[0552] (iii) a C₂₋₆ alkenyl group (e.g., allyl, 2-methyl-propenyl,etc.)[this C₂₋₆ alkenyl group may have a C₆₋₁₄ aryl (e.g., phenyl)],

[0553] (iv) a C₂₋₆ alkenyl group (e.g., propargyl, etc.),

[0554] (v) a C₃₋₆ cycloalkyl group (e.g., cyclopentyl, etc.),

[0555] (vi) a C₇₋₁₆ aralkyl group (e.g., benzyl, 3-phenylpropyl,5-phenylpentyl, etc.),

[0556] (vii) a C₁₋₆ alkyl-carbonyl group (e.g., acetyl, etc.),

[0557] (viii) a C₆₋₁₄ aryl-carbonyl group (e.g., benzoyl, etc.),

[0558] (ix) a C₇₋₁₆ aralkyl-carbonyl group (e.g., phenylacetyl, etc.),

[0559] (x) C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl,ethoxycarbonyl, etc.),

[0560] (xi) a mono- or di-C₁₋₆ alkyl-thiocarbamoyl group (e.g.,methylthiocarbamoyl, dimethylthiocarbamoyl, etc.),

[0561] (xii) an optionally halogenated C₁₋₆ alkyl-sulfonyl group (e.g.,methylsulfonyl, etc.),

[0562] (xiii) a 4- to 10-membered aromatic heterocyclic group containing1 to 4 heteroatom(s) selected from nitrogen, sulfur, oxygen atoms andthe like in addition to carbon atoms (e.g., tetrazolyl, etc.)

[0563] [this heterocyclic ring may have a C₆₋₁₄ aryl (e.g., phenyl)],

[0564] [X═nitrogen atom]

[0565] <1> a hydrogen atom,

[0566] <2> a C₁₋₆ alkyl group (e.g., methyl, ethyl, etc.)

[0567] [this C₁₋₆ alkyl group may have a C₁₋₆ alkoxy-carbonyl], <3> aformyl,

[0568] <4> a C₁₋₆ alkyl-carbonyl group (e.g., acetyl, propionyl, etc.),

[0569] <5> a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl,ethoxycarbonyl, etc.),

[0570] <6> a carbamoyl group,

[0571] <7> a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g.,methylcarbamoyl, dimethylcarbamoyl, etc.),

[0572] <8> a C₁₋₆ alkyl-sulfonyl group (e.g., methylsulfonyl),

[0573] [X═sulfur atom]

[0574] <1> a C₁₋₆ alkyl group (e.g., methyl, ethyl, etc.),

[0575] <2> a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g.,methylcarbamoyl, dimethylcarbamoyl),

[0576] [X═bond]

[0577] <1> a hydrogen atom,

[0578] <2> a C₁₋₆ alkyl group (e.g. methyl),

[0579] <3> a halogen atom (e.g., chlorine atom).

[0580] An “optionally substituted hydrocarbon group” represented by R⁶and R⁷ may be one similar to an “optionally substituted hydrocarbongroup” exemplified as a substituent on Ring A, and a C₁₋₆ alkyl group(e.g., methyl, ethyl, etc.) is preferred, with a methyl group beingpreferred especially.

[0581] An “optionally substituted 3- to 8-membered ring” formed by R⁶and R⁷ together with the adjacent carbon atom may be one similar to an“optionally substituted 3- to 8-membered ring” formed by R² and R³together with the adjacent carbon atom described above, and among suchgroups an optionally substituted 3- to 8-membered homocyclic ring ispreferred, with a C₃₋₈ cycloalkane (for example, cyclobutane,cyclopentane, cyclohexane, cycloheptane, cyclooctane) being preferred,and a 5- or 6-membered homocyclic ring such as cyclopentane andcyclohexane (especially cyclopentane) being preferred.

[0582] An “optionally substituted hydrocarbon group” represented by R⁸and R⁹ may be one similar to an “optionally substituted hydrocarbongroup” exemplified as a substituent on Ring A. Among such groups, thoseexemplified preferably are a C₁₋₆ alkyl group, C₁₋₆ alkenyl group orC₁₋₆ alkynyl group each of which may have 1 to 5 substituent(s) selectedfrom (1) a halogen atom, (2) an optionally halogenated C₁₋₆ alkyl, (3)an optionally halogenated C₁₋₆ alkoxy, (4) an optionally halogenatedC₁₋₆ alkylthio, (5) a hydroxy, (6) an amino, (7) a mono-C₁₋₆ alkylamino,(8) a di-C₁₋₆ alkylamino and the like, with C₁₋₆ alkyl group (e.g.,methyl, ethyl, etc.) being preferred especially.

[0583] Preferably, each of R⁸ and R⁹ may for example be a hydrogen atom,C₁₋₆ alkyl group (e.g., methyl, ethyl), with a hydrogen atom beingpreferred especially.

[0584] An optionally oxidized sulfur atom represented by X is S, SO andSO₂ with S and SO being preferred.

[0585] An “optionally substituted nitrogen atom” represented by X is onesimilar to an “optionally substituted nitrogen atom” represented by Edescribed above, and those exemplified typically are (1) —NH—, (2)—N(C₁₋₆ alkyl)-(e.g., —N(methyl)-, —N(ethyl)-, —N(propyl)-,—N(isopropyl)-, etc.), (3) —N(C₆₋₁₄ aryl)-(e.g., —N(phenyl)-,—N(2-naphthyl)-, etc.), (4) —N(C₇₋₁₆ aralkyl)-(e.g., —N(benzyl)-,—N(phenethyl)-, etc.), with —NH— and —N(methyl)- being preferredespecially.

[0586] X is preferably a bond, O, S, SO, —NH—, —N(methyl)- and the like.

[0587] Y is (1) an optionally substituted methylene group, or (2) acarbonyl group.

[0588] A substituent on a methylene group may for example be a groupselected from Substituent Group A described above, and among such groupsthose preferred are one or two C₁₋₆ alkyl group(s) (e.g., methyl, ethyl,etc.), hydroxy group(s) and the like.

[0589] Y is preferably (1) a methylene group which may have one or twoC₁₋₆ alkyl group(s) (e.g., methyl, ethyl, ethyl) or (2) a carbonylgroup, with a methylene group which may have one or two methyl(s) beingpreferred, and a methylene group being especially preferred.

[0590] n is 0 or 1, with 0 being preferred.

[0591] As a compound according to the invention, any one of those listedbelow is preferred.

[0592] [Compound (I)-I]

[0593] Compound (I) wherein:

[0594] R¹ is a group represented by Formula:

[0595] wherein each symbol is defined as described above, or a grouprepresented by Formula:

[0596] wherein each symbol is defined as described above, each of R² andR³ is a hydrogen atom or optionally substituted hydrocarbon group, andR² and R³ may be taken together with the adjacent carbon atom to form anoptionally substituted 3- to 8-membered ring, R⁴ is a hydrogen atom,cyano group, optionally substituted hydrocarbon group, acyl group oroptionally substituted hydroxy group, R⁵ is an optionally substitutedhydrocarbon group, each of R⁶ and R⁷ is an optionally substitutedhydrocarbon group, and R⁶ and R⁷ are taken together with the adjacentcarbon atom to form an optionally substituted 3- to 8-membered ring,each of R⁸ and R⁹ is a hydrogen atom, X is an oxygen atom or optionallyoxidized sulfur atom, Y is a methylene group which may have one or twoC₁₋₆ alkyl groups, and n is 0 or 1.

[0597] [Compound (I)-II]

[0598] Compound (I) wherein:

[0599] R¹ is a group represented by Formula:

[0600] wherein each symbol is defined as described above, or a grouprepresented by Formula:

[0601] wherein each symbol is defined as described above, each of R² andR³ is a hydrogen atom or optionally substituted hydrocarbon group, andR² and R³ may be taken together with the adjacent carbon atom to form anoptionally substituted 3- to 8-membered homocyclic or heterocyclic ring,R⁴ is a hydrogen atom, R⁵ is an optionally substituted hydrocarbongroup, each of R⁶ and R⁷ is an optionally substituted hydrocarbon group,and R⁶ and R⁷ are taken together with the adjacent carbon atom to forman optionally substituted 3- to 8-membered homocyclic ring, each of R⁸and R⁹ is a hydrogen atom, X is an oxygen atom or sulfur atom, Y is amethylene and n is 0 or 1.

[0602] [Compound (I)-III]

[0603] Compound (I) wherein R¹ is,

[0604] (i) a C₆₋₁₄ aryl group which may have 1 to 3 substituent(s)selected from the following (1) to (23):

[0605] (1) a halogen atom,

[0606] (2) a nitro group,

[0607] (3) a C₁₋₆ alkyl group (e.g., methyl, isopropyl, tert-butyl andthe like)

[0608] [this C₁₋₆ alkyl group may have a substituent selected from ahalogen atom, cyano, carbamoyl, C₁₋₆ alkyl-carbamoyl, C₁₋₆alkyl-carbonyloxy, C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkyl-carbamoyl, (5- or6-membered heterocyclic ring (e.g., 5- or 6-membered heterocyclic ringcontaining 1 to 3 heteroatom(s) selected from nitrogen, sulfur, oxygenatoms and the like in addition to carbon atoms such as pyridyl))-C₁₋₆alkyl-carbamoyl, C₁₋₆ alkylsulfonylamino, C₁₋₆ alkoxy-carbonyl andcarboxy, etc.],

[0609] (4) a C₃₋₆ cycloalkyl group (e.g., cyclohexyl),

[0610] (5) a C₆₋₁₄ aryl group (e.g., phenyl)

[0611] [this C₆₋₁₄ aryl group may have a substituent selected fromamino, carboxy, C₁₋₆ alkoxy-carbonyl, carbamoyl, mono- or di-C₁₋₆alkylcarbamoyl, formylamino, C₁₋₆ alkyl-carbonylamino which may have ahalogen atom or carboxy (e.g., acetylamino, propionylamino,trifluoroacetylamino, pivaloylamino), C₆₋₁₄ aryl-carbonylamino (e.g.,benzoylamino), C₁₋₆ alkoxy-carbonylamino (e.g., methoxycarbonylamino),ureido, mono- or di-C₁₋₆ alkylureido, C₁₋₆ alkylsulfonylamino (e.g.,methylsulfonylamino, etc.), (C₁₋₆ alkyl) (C₁₋₆ alkylsulfonyl) amino(e.g., methyl(methylsulfonyl)amino), (C₁₋₆ alkyl) (C₁₋₆alkyl-carbonyl)amino (e.g., methyl(acetyl)amino, etc.), C₁₋₆alkoxy-carbonyl-C₁₋₆ alkylamino (e.g., 2-ethoxycarbonyl-2-propylamino,etc.), C₆₋₁₄ aralkyloxy-carbonylamino (e.g., benzyloxycarbonylamino),C₁₋₆ alkyl-carbonylamino-C₁₋₆ alkyl-carbonylamino (e.g.,acetylaminoacetylamino), C₁₋₆ alkyloxy-C₁₋₆ alkyl-carbonylamino-C₁₋₆alkyl-carbonylamino (e.g., methoxyacetylaminoacetylamino), C₁₋₆alkylthio-C₁₋₆ alkyl-carbonylamino (e.g., methylthioacetylamino), C₁₋₆alkyl-sulfinyl-C₁₋₆ alkyl-carbonylamino (e.g.,methylsulfinylacetylamino), C₁₋₆ alkyl-sulfonyl-C₁₋₆ alkyl-carbonylamino(e.g., methylsulfonylacetylamino), C₆₋₁₄ aryloxy-carbonylamino (e.g.,phenoxycarbonylamino), hydroxy-C₁₋₆ alkyl-carbamoyl (e.g.,hydroxymethylcarbamoyl, hydroxyethylcarbamoyl), and may have asubstituent selected especially from amino carboxy, C₁₋₆alkoxy-carbonyl, carbamoyl, mono- or di-C₁₋₆ alkylcarbamoyl,formylamino, C₁₋₆ alkyl-carbonylamino which may have a halogen atom orcarboxy (e.g., acetylamino, propionylamino, trifluoroacetylamino,pivaloylamino), C₁₋₆ alkoxy-carbonylamino (e.g., methoxycarbonylamino),ureido, C₁₋₆ alkylsulfonylamino (e.g., methylsulfonylamino), (C₁₋₆alkyl)(C₁₋₆ alkylsulfonyl)amino (e.g., methyl(methylsulfonyl)amino,etc.), (C₁₋₆ alkyl)(C₁₋₆ alkyl-carbonyl)amino (e.g.,methyl(acetyl)amino, etc.), C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkylamino (e.g.,2-ethoxycarbonyl-2-propylamino, etc.), C₆₋₁₄ aralkyloxy-carbonylamino(e.g., benzyloxycarbonylamino) and the like],

[0612] (6) a C₁₋₆ alkoxy group which may have a halogen atom or C₁₋₆alkoxy-C₆₋₁₄ aryl (e.g., methoxy, trifluoromethoxy, isopropoxy,2-(4-methoxyphenyl)ethoxy, etc.),

[0613] (7) a C₆₋₁₄ aryloxy group (e.g., phenoxy),

[0614] (8) a C₁₋₆ alkylthio group which may have a carbamoyl (e.g.,methylthio, carbamoylmethylthio),

[0615] (9) a C₁₋₆ alkylsulfinyl group which may have a carbamoyl (e.g.,methylsulfinyl, carbamoylmethylsulfinyl),

[0616] (10) a C₆₋₁₄ arylthio group (e.g., phenylthio),

[0617] (11) a hydroxy group,

[0618] (12) a 4- to 14-membered heterocyclic group containing 1 to 4heteroatom(s) selected from nitrogen, sulfur, oxygen atoms and the likein addition to carbon atoms (e.g., pyrrolidinyl, piperidyl,isoindolinyl, furyl, thienyl, pyridyl, quinolyl, benzofuranyl,pyrimidinyl, tetrazolyl, imidazolidinyl, isothiazolidinyl,thiadiazolidinyl, azethinyl, etc.),

[0619] [this heterocyclic group may have a substituent selected fromoxo, carboxy-C₁₋₆ alkyl, C₁₋₆ alkyl-carbonyloxy-C₁₋₆ alkyl, C₁₋₆ alkyl,C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkyl, C₁₋₆ alkoxy-carbonyl, carbamoyl-C₁₋₆alkyl, C₁₋₆ alkyl-carbamoyl-C₁₋₆ alkyl, etc.],

[0620] (13) a carboxy group,

[0621] (14) a group represented by Formula: —CO—Hal (Hal is a halogenatom) (e.g., chloroformyl),

[0622] (15) a C₁₋₆ alkyl-carbonyl group (e.g., acetyl, etc.),

[0623] (16) a C₁₋₆ alkyl-sulfonyl group (e.g., methylsulfonyl, etc.),

[0624] (17) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl, etc.),

[0625] (18) a sulfamoyl group

[0626] [this sulfamoyl group may have 1 or 2 substituent(s) selectedfrom C₁₋₆ alkyl, carbamoyl-C₁₋₆ alkyl, C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkyl,(5- to 7-membered heterocyclic group which may have an oxo group (e.g.,5- to 7-membered heterocyclic group containing 1 to 3 heteroatom(s)selected from nitrogen, sulfur, oxygen atoms and the like in addition tocarbon atoms such as pyridyl, pyrrolidinyl hexahydroazepinyl))-C₁₋₆alkyl, C₁₋₆ alkyl-carbonylamino-C₆₋₁₄ aryl],

[0627] (19) a group represented by Formula: —NR^(a)R^(b)

[0628] [each of R^(a) and R^(b) is (i) a hydrogen atom, (ii) a C₁₋₆alkyl, (iii) a (5- or 6-membered heterocyclic ring (e.g., 5- or6-membered heterocyclic ring containing 1 to 3 heteroatom(s) selectedfrom nitrogen, sulfur, oxygen atoms and the like in addition to carbonatoms such as pyridyl))-C₁₋₆ alkyl, (iv) a C₁₋₆ alkoxy-carbonyl-C₁₋₆alkyl, (v) a di-C₁₋₆ alkylamino-methylene-sulfamoyl-C₁₋₆ alkyl, (vi) acarbamoyl-C₁₋₆ alkyl, (vii) a sulfamoyl-C₁₋₆ alkyl, (viii) a C₁₋₆alkyl-sulfonyl, (ix) a C₁₋₆ alkoxy-carbonyl, (x) a di-C₁₋₆alkoxy-carbonyl-C₂₋₆ alkenyl, (xi) a C₆₋₁₄ aryl, (xii) a 5- or6-membered heterocyclic ring (e.g., 5- or 6-membered heterocyclic ringcontaining 1 to 3 heteroatom(s) selected from nitrogen, sulfur, oxygenatoms and the like in addition to carbon atoms such as pyridyl), [this5- or 6-membered heterocyclic group may have a substituent selected fromamino, C₁₋₆ alkyl-carboxamido and C₁₋₆ alkyl-sulfonylamino and thelike], (xiii) an optionally halogenated C₁₋₆ alkyl-carbonyl, (xiv) aC₁₋₆ alkylthio-C₁₋₆ alkyl-carbonyl, (xv) a C₁₋₆ alkylsulfinyl-C₁₋₆alkyl-carbonyl, (xvi) a C₁₋₆ alkylsulfonyl-C₁₋₆ alkyl-carbonyl, (xvii)an amino-C₁₋₆ alkyl-carbonyl, (xviii) an optionally halogenated C₁₋₆alkyl-carbonyl-amino-C₁₋₆ alkyl-carbonyl, (xix) a C₆₋₁₄ aryl-carbonyl,(xx) a carboxy-C₆₋₁₄ aryl-carbonyl, (xxi) an optionally C₁₋₆alkyl-esterified phosphono-C₁₋₆ alkyl-C₆₋₁₄ aryl-carbonyl, (xxii) a (5-or 6-membered heterocyclic ring (e.g., 5- or 6-membered heterocyclicring containing 1 to 3 heteroatom(s) selected from nitrogen, sulfur,oxygen atoms and the like in addition to carbon atoms such aspyrrolidinyl, pyridyl) which may have a halogen atom, oxo or a C₁₋₆alkoxy-carbonyl)-carbonyl, (xxiii) a (5- or 6-membered heterocyclic ring(e.g., 5- or 6-membered heterocyclic ring containing 1 to 3heteroatom(s) selected from nitrogen, sulfur, oxygen atoms and the likein addition to carbon atoms such as pyridyl))-C₁₋₆ alkyl-carbonyl,(xxiv) a C₆₋₁₄ aryl-oxy-carbonyl, (xxv) a carboxy-C₁₋₆ alkyl, (xxvi) acarbamoyl, (xxvii) an optionally halogenated C₁₋₆ alkylcarbamoyl,(xxviii) a C₆₋₁₄ arylcarbamoyl which may have a C₁₋₆alkyl-carbonylamino, (xxix) a (5- or 6-membered heterocyclic ring (e.g.,5- or 6-membered heterocyclic ring containing 1 to 3 heteroatom(s)selected from nitrogen, sulfur, oxygen atoms and the like in addition tocarbon atoms such as pyridyl))-carbamoyl, (xxx) a C₂₋₆ alkenyl-carbonyl,(xxxi) a (5- or 6-membered heterocyclic ring (e.g., 5- or 6-memberedheterocyclic ring containing 1 to 3 heteroatom(s) selected fromnitrogen, sulfur, oxygen atoms and the like in addition to carbon atomssuch as pyrrolidinyl) which may have an oxo group)-amino-C₁₋₆alkyl-carbonyl, (xxxii) a (5- or 6-membered heterocyclic ring (e.g., 5-or 6-membered heterocyclic ring containing 1 to 3 heteroatom(s) selectedfrom nitrogen, sulfur, oxygen atoms and the like in addition to carbonatoms such as pyrrolidinyl) which may have an oxo group)(Cl₆ alkyl)amino-C₁₋₆ alkyl-carbonyl, (xxxiii) a (5- or 6-membered heterocyclicring (e.g., 5- or 6-membered heterocyclic ring containing 1 to 3heteroatom(s) selected from nitrogen, sulfur, oxygen atoms and the likein addition to carbon atoms such as pyrrolidinyl) which may have an oxogroup) (C₁₋₆ alkylcarbonyl) amino-C₁₋₆ alkyl-carbonyl, (xxxiv) a C₁₋₆alkylthio-C₁₋₆ alkylcarbonyl (sulfur atom may be oxidized), (xxxv) anoptionally halogenated C₁₋₆ alkylsulfonyl, (xxxvi) a sulfamoyl, (xxxvii)a C₁₋₆ alkylsulfamoyl and the like],

[0629] (20) a group represented by Formula: —C(═O)NR^(c)R^(d)

[0630] [each of R^(c) and R^(d) is (i) a hydrogen atom, (ii) a C₁₋₆alkyl, (iii) a 5- or 6-membered heterocyclic ring (e.g., 5- or6-membered heterocyclic ring containing 1 to 3 heteroatom(s) selectedfrom nitrogen, sulfur, oxygen atoms and the like in addition to carbonatoms such as pyridyl, imidazolyl)-C₁₋₆ alkyl, (iv) a carboxy-C₁₋₆alkyl,(v) a C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkyl, (vi) a di-C₁₋₆ alkylamino-C₁₋₆alkyl, (vii) a carbamoyl-C₁₋₆ alkyl, (viii) a C₁₋₆ alkylcarbamoyl-C₁₋₆alkyl, (ix) a (5- or 6-membered heterocyclic ring (e.g., 5- or6-membered heterocyclic ring containing 1 to 3 heteroatom(s) selectedfrom nitrogen, sulfur, oxygen atoms and the like in addition to carbonatoms such as pyridyl))-C₁₋₆ alkylcarbamoyl-C₁₋₆ alkyl, (x) a (5- or6-membered heterocyclic ring (e.g., 5- or 6-membered heterocyclic ringcontaining 1 to 3 heteroatom(s) selected from nitrogen, sulfur, oxygenatoms and the like in addition to carbon atoms such aspyridyl))-amino-C₁₋₆ alkyl, (xi) a sulfamoyl-C₆₋₁₄ aryl-C₁₋₆ alkyl,(xii) a C₆₋₁₄ aryl which may have C₁₋₆ alkoxy, (xiii) an optionally C₁₋₆alkyl-esterified phosphono-C₁₋₆ alkyl-C₆₋₁₄ aryl, (xiv) a 4- to10-membered heterocyclic group (e.g., 4- to 10-membered heterocyclicring containing 1 to 3 heteroatom(s) selected from nitrogen, sulfur,oxygen atoms and the like in addition to carbon atoms such as azethinyl,pyrrolidinyl, piperidinyl, hexahydroazepinyl, pyridyl, pyrimidinyl,pyrazinyl, pyridazinyl, 1-azabicyclo[2.2.2]octo-3-yl, etc.) [this 4- to10-membered heterocyclic group may have 1 to 2 substituent(s) selectedfrom a halogen atom, C₁₋₆ alkyl and oxo, etc.], (xv) a C₆₋₁₄aryl-carbamoyl-C₁₋₆ alkyl, (xvi) a hydroxy-C₁₋₆ alkyl or (xvii) a (5- or6-membered heterocyclic ring (e.g., 5- or 6-membered heterocyclic ringcontaining 1 to 3 heteroatom(s) selected from nitrogen, sulfur, oxygenatoms and the like in addition to carbon atoms such as pyrrolidinyl,pyridyl) which may have a oxo group)-carbamoyl-C₁₋₆ alkyl; and R^(c) ispreferably a hydrogen atom],

[0631] (21) a cyano group,

[0632] (22) a mono- or di-C₁₋₆ alkylcarbamoylthio group (e.g.,dimethylcarbamoylthio),

[0633] (23) a mono- or di-C₁₋₆ alkylthiocarbamoyloxy group (e.g.,dimethylthiocarbamoyloxy);

[0634] (ii) a 4- to 14-membered heterocyclic group containing 1 to 4heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms which may contain 1 to 3 substituent(s)selected from the following (1) to (8):

[0635] (1) a halogen atom,

[0636] (2) a C₁₋₆ alkyl group [this alkyl may have a substituentselected from carboxy, C₁₋₆ alkoxy, C₁₋₆ alkoxy-carbonyl, mono-C₁₋₆alkyl-amino, di-C₁₋₆ alkyl-amino, carbamoyl, C₁₋₆ alkyl-carbamoyl whichmay have a hydroxy, 4- to 10-membered heterocyclic group containing 1 to3 heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms which may have oxo, (4- to 10-memberedheterocyclic ring containing 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms in addition to carbonatoms)-carbamoyl, carbamoyl-C₁₋₆ alkyl-carbamoyl],

[0637] (3) a C₁₋₆ alkoxy group,

[0638] (4) a C₆₋₁₄ aryl group,

[0639] (5) a C₇₋₁₆ aralkyl group [this C₇₋₁₆ aralkyl group may have asubstituent selected from carboxy, C₁₋₆ alkoxy-carbonyl, carbamoyl, C₁₋₆alkyl-carbamoyl which may have hydroxy, (4- to 10-membered heterocyclicring containing 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms in addition to carbon atoms)-carbamoyl],

[0640] (6) a 4- to 10-membered heterocyclic group containing 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms [this 4- to 10-membered heterocyclic group mayhave a substituent selected from a C₁₋₆ alkyl, C₁₋₆ alkoxy-carbonyl,carbamoyl, oxo, 4- to 10-membered heterocyclic group containing 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms],

[0641] (7) an oxo group,

[0642] (8) an oxide group;

[0643] (iii) a C₃₋₆ cycloalkyl group; or,

[0644] (iv) a group represented by Formula: —L′—R^(1a′) (L′ ismethylene, carbonyl or an optionally substituted nitrogen atom, R^(1a′)is (1) a hydrogen atom, (2) a C₆₋₁₄ aryl group which may have 1 to 5substituent(s) selected from a C₁₋₆ alkyl and C₁₋₆ alkoxy, (3) a hydroxygroup which may be substituted by a C₁₋₆ alkyl group, (4) a C₁₋₆alkyl-amino group which may be substituted by a 4- to 10-memberedheterocyclic ring containing 1 to 3 heteroatom(s) selected fromnitrogen, oxygen and sulfur atoms in addition to carbon atoms, (6) aC₆₋₁₄ aryl-amino group or (7) a (4- to 10-membered heterocyclic ringcontaining 1 to 3 heteroatom(s) selected from nitrogen, oxygen andsulfur atoms in addition to carbon atoms)-amino group),

[0645] each of R² and R³ is (1) a hydrogen atom, (2) a C₁₋₆ alkyl groupwhich may be substituted by <1> a halogen atom, <2> an optionallysubstituted hydroxy group (for example, a hydroxy group which may besubstituted by a substituent selected from a C₁₋₆ alkyl, C₁₋₆alkyl-carbonyl, C₁₋₆ alkylsulfonyl and C₇₋₁₆ aralkyl), <3> an optionallysubstituted amino group (for example, an amino group which may besubstituted by 1 or 2 C₁₋₆ alkyl, C₁₋₆ alkyl-carbonyl and C₆₋₁₄aryl-carbonyl, etc.), <4> an optionally substituted 4- to 10-memberedheterocyclic group (for example, a 4- to 10-membered heterocyclic groupcontaining 1 to 3 heteroatom(s) selected from nitrogen, oxygen, sulfuratoms and the like in addition to carbon atoms which may have an oxogroup (e.g., phthalimido, imidazolinyl, piperidinyl, pyrrolidinyl)), <5>an optionally substituted thio group (for example, a thio group whichmay have a C₁₋₆ alkyl), <6> a C₁₋₆ alkyl-sulfinyl group or <7> a C₁₋₆alkyl-sulfonyl group, or (3) a C₁₋₆ alkoxy-carbonyl group,

[0646] R² and R³ may be taken together with the adjacent carbon atom toform a C₃₋₈ cycloalkane,

[0647] R⁴ is (i) a hydrogen atom, (ii) a cyano group, (iii) a C₁₋₆ alkylgroup [this C₁₋₆ alkyl group may have a substituent selected from (1) ahalogen atom, (2) a cyano group, (3) a C₁₋₆ alkoxy group, (4) a hydroxygroup, (5) an amino group, (6) a mono-C₁₋₆ alkylamino group, (7) adi-C₁₋₆ alkylamino group, (8) a tri-C₁₋₆ alkylammonium group, (8) a 4-to 10-membered heterocyclic group containing 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms in addition to carbonatoms which may have an oxo, (9) a C₆₋₁₄ arylthio, (10) an ureido, (11)a carboxy, (12) a carbamoyl, (13) a C₁₋₆ alkoxy-carbonyl, (14) amono-C₁₋₆ alkyl-carbamoyl, (15) a formylamino and (16) a C₁₋₆alkyl-carboxamido], (iv) a C₂₋₆ alkenyl group or (v) a formyl group;

[0648] X is a bond, oxygen atom, optionally oxidized sulfur atom, —NH—or —N(methyl)-,

[0649] R⁵ is,

[0650] when X is a bond, then (i) a hydrogen atom, (ii) a C₁₋₆ alkylgroup or (iii) a halogen atom,

[0651] when X is an oxygen atom, then (i) a hydrogen atom, (ii) a C₁₋₆alkyl group [this C₁₋₆ alkyl group may have a substituent selected from(1) a halogen atom, (2) a hydroxy group, (3) an amino group, (4) acarboxy, (5) a carbamoyl, (6) a C₁₋₆ alkoxy-carbonyl, (7) a mono-C₁₋₆alkyl-carbamoyl, (8) a di-C₁₋₆ alkyl-carbamoyl, (9) a 4- to 10-memberedheterocyclic group containing 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms in addition to carbon atoms], (iii) aC₂₋₆ alkenyl group [this C₂₋₆ alkenyl group may have a C₆₋₁₄ aryl], (iv)a C₂₋₆ alkynyl group, (v) a C₃₋₆ cycloalkyl group, (vi) a C₇₋₁₆ aralkylgroup, (vii) a C₁₋₆ alkyl-carbonyl group, (viii) a C₆₋₁₄ aryl-carbonylgroup, (ix) a C₁₋₆ alkoxy-carbonyl group, (x) a mono- or di-C₁₋₆alkyl-thiocarbamoyl group, (xi) an optionally halogenated C₁₋₆alkyl-sulfonyl group or (xii) a 4- to 10-membered heterocyclic groupcontaining 1 to 4 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms in addition to carbon atoms [this heterocyclic group mayhave a C₆₋₁₄ aryl],

[0652] when X is an optionally oxidized sulfur, then (i) a C₁₋₆ alkylgroup or (ii) a mono- or di-C₁₋₆ alkyl-carbamoyl group,

[0653] when X is —NH— or —N(methyl)-, then (i) a hydrogen atom, (ii) aC₁₋₆ alkyl group [this C₁₋₆ alkyl group may have a C₁₋₆alkoxy-carbonyl], (iii) formyl, (iv) a C₁₋₆ alkyl-carbonyl group, (v) aC₁₋₆ alkoxy-carbonyl group, (vi) a carbamoyl group, (vii) a mono- ordi-C₁₋₆ alkyl-carbamoyl group or (viii) a C₁₋₆ alkyl-sulfonyl group,

[0654] each of R⁶ and R⁷ is a hydrogen atom or C₁₋₆ alkyl group,

[0655] R⁶ and R⁷ may be taken together with the adjacent carbon atom toform a C₃₋₈ cycloalkane,

[0656] Each of R⁸ and R⁹ is a hydrogen atom or a C₁₋₆ alkyl group,

[0657] Y is <1> a methylene group which may have 1 or 2 C₁₋₆ alkyl orhydroxy group or <2> a carbonyl group,

[0658] n is 0 or 1.

[0659] [Compound (I)-IV]

[0660] Compound (I) wherein R¹ is,

[0661] (i) a C₆₋₁₄ aryl group which may have 1 to 3 substituent(s)selected from the following (1) to (20):

[0662] (1) a halogen atom,

[0663] (2) a nitro group,

[0664] (3) a C₁₋₆ alkyl group [this C₁₋₆ alkyl group may have asubstituent selected from a halogen atom, cyano, carbamoyl, C₁₋₆alkyl-carbamoyl, C₁₋₆ alkyl-carbonyloxy, C₁₋₆ alkoxy-carbonyl-C₁₋₆alkyl-carbamoyl, (5- or 6-membered heterocyclic ring containing 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms)-C₁₋₆ alkyl-carbamoyl, C₁₋₆ alkylsulfonylamino,C₁₋₆ alkoxy-carbonyl and carboxy],

[0665] (4) a C₃₋₆ cycloalkyl group,

[0666] (5) a C₆₋₁₄ aryl group

[0667] [this C₆₋₁₄ aryl group may have a substituent selected fromamino, optionally halogenated C₁₋₆ alkyl-carbonylamino, ureido, C₁₋₆alkylsulfonylamino, (C₁₋₆ alkyl)(C₁₋₆ alkylsulfonyl) amino, C₁₋₆alkoxy-carbonyl-C₁₋₆ alkylamino],

[0668] (6) a C₁₋₆ alkoxy group which may have a halogen atom or C₁₋₆alkoxy-C₆₋₁₄ aryl,

[0669] (7) a C₆₋₁₄ aryloxy group,

[0670] (8) a C₁₋₆ alkylthio group,

[0671] (9) a C₁₋₆ alkylsulfinyl group,

[0672] (10) a C₆₋₁₄ arylthio group,

[0673] (11) a hydroxy group,

[0674] (12) a 5- to 14-membered heterocyclic group containing-1 to 4heteroatom(s) selected from nitrogen, sulfur and oxygen atoms

[0675] [this heterocyclic group may have a substituent selected fromoxo, carboxy-C₁₋₆ alkyl, C₁₋₆ alkyl-carbonyloxy-C₁₋₆ alkyl, C₁₋₆alkoxy-carbonyl-C₁₋₆ alkyl, C₁₋₆ alkyl-carbamoyl-C₁₋₆ alkyl],

[0676] (13) a carboxy group,

[0677] (14) a group represented by Formula: —CO—Hal (Hal is a halogentom),

[0678] (15) a C₁₋₆ alkyl-carbonyl group,

[0679] (16) a C₁₋₆ alkyl-sulfonyl group,

[0680] (17) a C₁₋₆ alkoxy-carbonyl group,

[0681] (18) a sulfamoyl group [this sulfamoyl group may have asubstituent selected from a C₁₋₆ alkyl, carbamoyl-C₁₋₆ alkyl, (5- or6-membered heterocyclic ring containing 1 to 3 heteroatom(s) selectedfrom nitrogen, sulfur and oxygen atoms in addition to carbon atoms)-C₁₋₆alkyl],

[0682] (19) a group represented by Formula: NR^(a)R^(b) [each of R^(a)and R^(b) is (i) a hydrogen atom, (ii) a C₁₋₆ alkyl, (iii) a (5- or6-membered heterocyclic ring containing 1 to 3 heteroatom(s) selectedfrom nitrogen, sulfur and oxygen atoms in addition to carbon atoms)-C₁₋₆alkyl, (iv) a C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkyl, (v) a di-C₁₋₆alkylamino-methylene-sulfamoyl-C₁₋₆ alkyl, (vi) a carbamoyl-C₁₋₆ alkyl,(vii) a sulfamoyl-C₁₋₆ alkyl, (viii) a C₁₋₆ alkyl-sulfonyl, (ix) a C₁₋₆alkoxy-carbonyl, (x) a di-C₁₋₆ alkoxy-carbonyl-C₂₋₆ alkenyl, (xi) aC₆₋₁₄ aryl, (xii) a 5- or 6-membered heterocyclic group containing 1 to3 heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms [this 5- or 6-membered heterocyclic group mayhave a substituent selected from amino, C₁₋₆ alkyl-carboxamido and C₁₋₆alkyl-sulfonylamino], (xiii) an optionally halogenated C₁₋₆alkyl-carbonyl, (xiv) a C₁₋₆ alkylthio-C₁₋₆ alkyl-carbonyl, (xv) a C₁₋₆alkylsulfinyl-C₁₋₆ alkyl-carbonyl, (xvi) a C₁₋₆ alkylsulfonyl-C₁₋₆alkyl-carbonyl, (xvii) an amino-C₁₋₆ alkyl-carbonyl, (xviii) anoptionally halogenated C₁₋₆ alkyl-carbonyl-amino-C₁₋₆ alkyl-carbonyl,(xix) a C₆₋₁₄ aryl-carbonyl, (xx) a carboxy-C₆₋₁₄ aryl-carbonyl, (xxi)an optionally C₁₋₆ alkyl-esterified phosphono-C₁₋₆ alkyl-C₆₋₁₄aryl-carbonyl, (xxii) a 5-or 6-membered heterocyclic ring containing 1to 3 heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms, (xxiii) a (5- or 6-membered heterocyclic ringcontaining 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms in addition to carbon atoms which may have a C₁₋₆alkoxy-carbonyl)-C₁₋₆ alkyl-carbonyl, (xxiv) a C₆₋₁₄ aryl-oxy-carbonyl,(xxv) a carboxy-C₁₋₆ alkyl or (xxvi) a carbamoyl],

[0683] (20) a group represented by Formula: —C(═O)NR^(c)R^(d) [each ofR^(c) and R^(d) is (1) a hydrogen atom, (ii) a C₁₋₆ alkyl, (iii) a (5-or 6-membered heterocyclic ring containing 1 to 3 heteroatom(s) selectedfrom nitrogen, sulfur and oxygen atoms in addition to carbon atoms)-C₁₋₆alkyl, (iv) a carboxy-C₁₋₆ alkyl, (v) a C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkyl,(vi) a di-C₁₋₆ alkylamino-C₁₋₆ alkyl, (vii) a carbamoyl-C₁₋₆ alkyl,(viii) a C₁₋₆ alkylcarbamoyl-C₁₋₆ alkyl, (ix) a (5- or 6-memberedheterocyclic group containing 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms)-C₁₋₆ alkyl-carbamoyl-C₁₋₆ alkyl, (x)a (5- or 6-membered heterocyclic group containing 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms in addition to carbonatoms)-amino-C₁₋₆ alkyl, (xi) a sulfamoyl-C₆₋₁₄ aryl-C₁₋₆ alkyl, (xii) aC₆₋₁₄ aryl which may have a C₁₋₆ alkoxy, (xiii) a C₁₋₆ alkyl-C₆₋₁₄ arylwhich may have an optionally C₁₋₆ alkyl-esterified phosphono group,(xiv) a 4- to 10-membered heterocyclic ring containing 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms [this heterocyclic group may have 1 or 2substituent(s) selected from a halogen atom, C₁₋₆ alkyl and oxo] or (xv)a C₆₋₁₄ aryl-carbamoyl-C₁₋₆ alkyl;

[0684] (ii) a 5- to 14-membered heterocyclic group containing 1 to 4heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms which may contain 1 to 3 substituent(s)selected from the following (1) to (8):

[0685] (1) a halogen atom,

[0686] (2) a C₁₋₆ alkyl group [this alkyl may have a substituentselected from carboxy, C₁₋₆ alkoxy, C₁₋₆ alkoxy-carbonyl, mono-C₁₋₆alkyl-amino, di-C₁₋₆ alkyl-amino, carbamoyl, C₁₋₆ alkyl-carbamoyl whichmay have a hydroxy, 4- to 10-membered heterocyclic group containing 1 to3 heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms which may have oxo, (4- to 10-memberedheterocyclic ring containing 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms in addition to carbonatoms)-carbamoyl, carbamoyl-C₁₋₆ alkyl-carbamoyl],

[0687] (3) a C₁₋₆ alkoxy group,

[0688] (4) a C₆₋₁₄ aryl group,

[0689] (5) a C₇₋₁₆ aralkyl group [this C₇₋₁₆ aralkyl group may have asubstituent selected from carboxy, C₁₋₆ alkoxy-carbonyl, carbamoyl, C₁₋₆alkyl-carbamoyl which may have a hydroxy, (4- to 10-memberedheterocyclic ring containing 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms in addition to carbonatoms)-carbamoyl],

[0690] (6) a 4- to 10-membered heterocyclic group containing 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms [this 4- to 10-membered heterocyclic group mayhave a substituent selected from a C₁₋₆ alkyl, C₁₋₆ alkoxy-carbonyl,carbamoyl, oxo, 4- to 10-membered heterocyclic group containing 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms],

[0691] (7) an oxo group,

[0692] (8) an oxide group;

[0693] (iii) a C₃₋₆ cycloalkyl group; or,

[0694] (iv) a group represented by Formula: —L′—R^(1a′) (L′ ismethylene, carbonyl or an optionally substituted nitrogen atom, R^(1a′)is (1) a hydrogen atom, (2) a C₆₋₁₄ aryl group which may have 1 to 5substituent(s) selected from a C₁₋₆ alkyl and C₁₋₆ alkoxy, (3) a hydroxygroup which may be substituted by a C₁₋₆ alkyl group, (4) a C₁₋₆alkyl-amino group which may be substituted by a 4- to 10-memberedheterocyclic ring containing 1 to 3 heteroatom(s) selected fromnitrogen, oxygen and sulfur atoms in addition to carbon atoms, (6) aC₆₋₁₄ aryl-amino group or (7) a (4- to 10-membered heterocyclic ringcontaining 1 to 3 heteroatom(s) selected from nitrogen, oxygen andsulfur atoms in addition to carbon atoms)-amino group),

[0695] each of R² and R³ is (1) a hydrogen atom, (2) an optionallyhalogenated C₁₋₆ alkyl group or (3) a C₁₋₆ alkoxy-carbonyl group,

[0696] R² and R³ may be taken together with the adjacent carbon atom toform a C₃₋₈ cycloalkane,

[0697] R⁴ is (i) a hydrogen atom, (ii) a C₁₋₆ alkyl group [this C₁₋₆alkyl group may have a substituent selected from (1) a halogen atom, (2)a cyano group, (3) a C₁₋₆ alkoxy group, (4) a hydroxy group, (5) anamino group, (6) a mono-C₁₋₆ alkylamino group, (7) a di-C₁₋₆ alkylaminogroup, (8) a tri-C₁₋₆ alkylammonium group, (8) a 4- to 10-memberedheterocyclic group containing 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms in addition to carbon atoms which mayhave an oxo, (9) a C₆₋₁₄ arylthio, (10) an ureido, (11) a carboxy, (12)a carbamoyl, (13) a C₁₋₆ alkoxy-carbonyl, (14) a mono-C₁₋₆alkyl-carbamoyl, (15) a formylamino, (16) a C₁₋₆ alkyl-carboxamido] or(iii) a C₂₋₆ alkenyl group;

[0698] X is a bond, oxygen atom, sulfur atom, —NH— or —N(methyl)-,

[0699] R⁵ is,

[0700] when X is a bond, then (i) a hydrogen atom, (ii) a C₁₋₆ alkylgroup or (iii) a halogen atom,

[0701] when X is an oxygen atom, then (i) a hydrogen atom, (ii) a C₁₋₆alkyl group [this C₁₋₆ alkyl group may have a substituent selected from(1) a halogen atom, (2) a hydroxy group, (3) an amino group, (4) acarboxy, (5) a carbamoyl, (6) a C₁₋₆ alkoxy-carbonyl, (7) a mono-C₁₋₆alkyl-carbamoyl, (8) a di-C₁₋₆ alkyl-carbamoyl, (9) a 4- to 10-memberedheterocyclic group containing 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms in addition to carbon atoms], (iii) aC₂₋₆ alkenyl group [this C₂₋₆ alkenyl group may have a C₆₋₁₄ aryl], (iv)a C₂₋₆ alkynyl group, (v) a C₃₋₆ cycloalkyl group, (vi) a C₇₋₁₆ aralkylgroup, (vii) a C₁₋₆ alkyl-carbonyl group, (viii) a C₆₋₁₄ aryl-carbonylgroup, (ix) a C₁₋₆ alkoxy-carbonyl group, (x) a mono- or di-C₁₋₆alkyl-thiocarbamoyl group, (xi) an optionally halogenated C₁₋₆alkyl-sulfonyl group or (xii) a 4- to 10-membered heterocyclic groupcontaining 1 to 4 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms in addition to carbon atoms [this heterocyclic group mayhave a C₆₋₁₄ aryl],

[0702] when X is a sulfur atom, then (i) a C₁₋₆ alkyl group or (ii) amono- or di-C₁₋₆ alkyl-carbamoyl group,

[0703] when X is —NH— or —N(methyl)-, then (i) a hydrogen atom, (ii) aC₁₋₆ alkyl group [this C₁₋₆ alkyl group may have a C₁₋₆alkoxy-carbonyl], (iii) formyl, (iv) a C₁₋₆ alkyl-carbonyl group, (v) aC₁₋₆ alkoxy-carbonyl group, (vi) a carbamoyl group, (vii) a mono- ordi-C₁₋₆ alkyl-carbamoyl group or (viii) a C₁₋₆ alkyl-sulfonyl group,

[0704] each of R⁶ and R⁷ is a hydrogen atom or C₁₋₆ alkyl group,

[0705] R⁶ and R⁷ may be taken together with the adjacent carbon atom toform a C₃₋₈ cycloalkane,

[0706] each of R⁸ and R⁹ is a hydrogen atom or a C₁₋₆ alkyl group,

[0707] Y is (1) a methylene group which may have a hydroxy group or (2)a carbonyl group,

[0708] n is 0 or 1.

[0709] [Compound (I)-V]

[0710] Compounds produced in Examples 1 to 588 or salts thereof.

[0711] [Compound (I)-VI]

[0712] Compounds produced in Examples 1 to 438 or salts thereof.

[0713] [Compound (I)-VII]

[0714] (i)2-(Methylsulfinyl)-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]acetamide,(ii)N-(methylsulfonyl)-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]methanesulfonamide,(iii)N-[2-(4-pyridinyl)ethyl]-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide,(iv)N-(2-amino-2-oxoethyl)-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide,(v)N-methyl-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide,(vi)N-ethyl-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide,(vii)N-[3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-3-yl]acetamide,(viii)N-(2-amino-1,1-dimethyl-2-oxoethyl)-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide,(ix)3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-N-methylbenzamide,(x)N-[2-amino-2-oxoethyl]-3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide,(xi)N-(2-amino-1,1-dimethyl-2-oxoethyl)-3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide,(xii)N-[3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]methanesulfonamide,(xiii)N-(hydroxymethyl)-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamideor its salts.

[0715] [Compound (I)-VIII]

[0716] (i)2-(Methylsulfinyl)-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]acetamide,(ii)N-(methylsulfonyl)-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]methanesulfonamide,(iii)N-[2-(4-pyridinyl)ethyl]-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide,(iv)N-(2-amino-2-oxoethyl)-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide,(v)N-methyl-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide,(vi)N-ethyl-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide,(vii)N-[3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-3-yl]acetamideor its salts.

[0717] A compound having a partial structure represented by Formula:

[0718] wherein — — — is a single bond or double bond employed in apharmaceutical composition according to the invention is typically acompound represented by Formula:

[0719] wherein each of Ring A, Ring B and Ring C may have a substituentsimilar to that described above, more typically a compound representedby Formula:

[0720] wherein — — — is a single bond or double bond and other symbolsare defined as descried above.

[0721] When — — — is a single bond, then N may have a hydrogen atom or asubstituent described above.

[0722] As Compound (A-1), (I-1) or (I′-1) according to the invention, acompound produced in any of Examples 1 to 588 and Reference Example 10to 12, 112, 134, 135, 138 and 139 is specifically employed.

[0723] A process for producing Compound (I) or (I′) according to theinvention is described below. It should be understood that Compound(Ia), (Ib) and (Ic) are encompassed in Compound (I).

[0724] Compound (I) and (I′) according to the invention can be obtainedfor example by the methods represented by Schemes 1 to 17 shown below oranalogous methods.

[0725] Compounds (A), (A-1), (I-1) and (I′-1) can be produced also inaccordance with the production methods described below.

[0726] Unless otherwise specified, each symbol in a compound shown in aformula in the following schemes is defined as described above. In theschemes, Compounds (II′) to (LII′), (LIII) to (LXII) and (LXIII′) to(LXIX′) encompass their respective salt forms, and such a salt may forexample be one similar to a salt of Compound (I) or (I′).

[0727] Compounds (II′), (III′), (VI′), (VIb′), (VII′), (VIIa′), (IX′),(XI′), (XII′), (XIII′), (XVIII′), (XVIIIa′), (XX′), (XXI′), (XXVII′),(XXIX′), (XXXI′), (XXXIII′), (XXXIIIa′), (XXXVII′), (XXXVIII′), (XL′),(XLI′), (XLVII′), (L′), (LI′), (LIII), (LVI), (LVIII), (LXIII′), (LXV′)and (LXVII′) may readily be available commercially, or may be producedby a method known per se or an analogous method.

[0728] Solvent referred to as general names employed in the followingreactions are, unless otherwise specified, alcohol including methanol,ethanol, 1-propanol, 2-propanol and tert-butyl alcohol, etc., etherincluding diethyl ether, diisopropyl ether, diphenyl ether,tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane, etc., hydrocarbonincluding benzene, toluene, cyclohexane and hexane, etc., amideincluding N,N-dimethylformamide, N,N-dimethylacetamide andhexamethylphosphoric triamide, etc., halogenated hydrocarbon includingdichloromethane, chloroform, carbon tetrachloride and1,2-dichloroethane, etc., nitrile including acetonitrile andpropionitrile, etc., ketone including acetone and ethyl methyl ketone,etc., organic acid including formic acid, acetic acid, propionic acid,trifluoroacetic acid and methanesulfonic acid, etc., aromatic amineincluding pyridine, 2,6-lutidine and quinoline, etc., sulfoxideincluding dimethyl sulfoxide, etc.

[0729] Bases referred to as general names employed in the followingreactions are, unless otherwise specified, inorganic base includingsodium hydroxide, potassium hydroxide, lithium hydroxide and bariumhydroxide, etc., basic salt including sodium carbonate, potassiumcarbonate, cesium carbonate, sodium hydrogen carbonate, sodium acetateand ammonium acetate, etc., aromatic amine including pyridine andlutidine, etc., tertiary amine including triethylamine, tripropylamine,tributylamine, N-ethyldiisopropylamine, cyclohexyldimethylamine,4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine,N-methylpyrrolidine and N-methylmorpholine, etc., alkaline metal hydrideincluding sodium hydride and potassium hydride, etc., metal amideincluding sodium amide, lithium diisopropylamide and lithiumhexamethyldisilazide, etc., alkyl metal including butyllithium andtert-butyllithium, etc., aryl metal including phenyllithium, etc., metalalkoxide including sodium methoxide, sodium ethoxide, sodiumtert-butoxide and potassium tert-butoxide, etc.

[0730] While a product can be used as a reaction solution or a crudematerial in the next reaction, it can be isolated from the reactionmixture according to a standard method, and can readily be purified byan ordinary separation procedure (e.g., recrystallization, distillation,chromatography, etc.).

[0731] Compound (IV′) can be produced by reacting Compound (II′) andCompound (III′) wherein R¹⁶ and R¹⁷ are optionally substitutedhydrocarbon groups which form a part of R⁷, and may be those similar toR⁷, and when R¹⁶ forms a homocyclic ring with R⁶ then it may have asubstituent similar to a substituent which may be possessed by a “3- to8-membered homocyclic ring” and W is a leaving group, if desired in thepresence of a base.

[0732] Said “leaving group” may for example be a hydroxy, halogen atom(for example, fluorine, chlorine, bromine, iodine, etc.), optionallyhalogenated C₁₋₅ alkylsulfonyloxy (for example, methanesulfonyloxy,ethanesulfonyloxy, trichloromethanesulfonyloxy, etc.), optionallysubstituted C₆₋₁₀ arylsulfonyloxy and the like. An “optionallysubstituted C₆₋₁₀ arylsulfonyloxy” may for example, a C₆₋₁₀arylsulfonyloxy (e.g., phenylsulfonyloxy, naphthylsulfonyloxy, etc.)which may have 1 to 3 substituent(s) selected from a C₁₋₆ alkyl (e.g.methyl, ethyl, etc.), C₁₋₆ alkoxy (e.g., methoxy, ethoxy, etc.) andnitro, and those exemplified typically are phenylsulfonyloxy,m-nitrophenylsulfonyloxy, p-toluenesulfonyloxy and the like.

[0733] The amount of Compound (III′) employed is about 1 to about 5moles, preferably about 1 to about 2 moles per mole of Compound (II′).

[0734] Said “base” may for example be an inorganic base, basic salt,aromatic amine, tertiary amine, metal hydride, metal amide and metalalkoxide, etc. The amount of a base employed is about 1 to about 5moles, preferably about 1 to about 2 moles per mole of Compound (II′).

[0735] This reaction is conducted advantageously using a solvent whichis inert to the reaction. While such a solvent is not limitedparticularly as long as the reaction is proceeded, it may for example bea solvent such as an alcohol, ether, hydrocarbon, amide, halogenatedhydrocarbon, nitrile, ketone and sulfoxide as well as a mixture thereof.

[0736] The reaction time is usually about 30 minutes to about 48 hours,preferably about 1 hour to about 24 hours. The reaction temperature isusually about −20 to about 150° C., preferably about 0 to about 100° C.

[0737] In addition to the reaction described above, Mitsunobu reaction(Synthesis, 1981, p1-27) can also be employed.

[0738] Said reaction allows Compound (II′) and Compound (III′) wherein Wis OH to react with each other in the presence of an azodicarboxylate(e.g., diethylazodicarboxylate, etc.) and a phosphine (e.g.,triphenylphosphine, tributylphosphine, etc.).

[0739] The amount of Compound (III′) wherein W is OH is about 1 to about5 moles, preferably about 1 to about 2 moles per mole of Compound (II′).

[0740] The amount of each of said “azodicarboxylate” and “phosphine”employed is about 1 to about 5 moles, preferably about 1 to about 2moles per mole of Compound (II′).

[0741] This reaction is conducted advantageously using a solvent whichis inert to the reaction. While such a solvent is not limitedparticularly as long as the reaction is proceeded, it may for example bea solvent such as an ether, hydrocarbon, amide, halogenated hydrocarbon,nitrile, ketone and sulfoxide as well as a mixture thereof.

[0742] The reaction time is usually about 5 minutes to about 48 hours,preferably about 10 minutes to about 24 hours. The reaction temperatureis usually about −20 to about 200° C., preferably about 0 to about 100°C.

[0743] Compound (V′) is produced by subjecting Compound (IV′) to aClaisen rearrangement.

[0744] This reaction is conducted advantageously without using a solventor with using a solvent which is inert to the reaction. While such asolvent is not limited particularly as long as the reaction isproceeded, it may for example be a solvent such as an alcohol,hydrocarbon, organic acid, ether, aniline (e.g., N,N-dimethylaniline,N,N-diethylaniline, etc.), phenol (e.g., 2,6-dimethylphenol, etc.) andhalogenated hydrocarbon as well as a mixture thereof.

[0745] This reaction may be conducted also using an acid catalyst ifdesired. Such an acid catalyst may be a Lewis acid such as aluminumchloride and boron tribromide, etc. The amount of an acid catalyst, forexample, when using a Lewis acid, is about 0.1 to about 20 moles,preferably about 0.1 to about 5 moles per mole of Compound (IV′). Thereaction time is usually about 30 minutes to about 24 hours, preferablyabout 1 hour to about 6 hours. The reaction temperature is usually about−70 to about 300° C., preferably about 150 to about 250° C.

[0746] Compound (VI′) can be produced by subjecting Compound (V′) to aring closure reaction in the presence of a protonic acid, Lewis acid oriodine. Such a protonic acid may for example be mineral acid such ashydrochloric acid, hydrobromic acid, sulfuric acid, etc., sulfonic acidsuch as methanesulfonic acid, trifluoromethanesulfonic acid,fluorosulfonic acid. Such a Lewis acid may for example be aluminumchloride, aluminum bromide, titanium (IV) chloride, tin (IV) chloride,zinc chloride, boron trichloride, boron tribromide and borontrifluoride, etc. While a protonic acid or Lewis acid is employedusually each alone, the both may be combined if necessary. When aprotonic acid is employed, it is used in an amount of about 1 to about200 moles, preferably about 1 to about 100 moles per mole of Compound(V′). When a Lewis acid is employed, it is used in an amount of about 1to about 5 moles, preferably about 1 to about 3 moles per mole ofCompound (V′). When iodine is employed, it is used in an amount of about0.05 to about 1 moles, preferably about 0.1 to about 0.5 moles per moleof Compound (V′).

[0747] This reaction is conducted advantageously using a solvent whichis inert to the reaction. While such a solvent is not limitedparticularly as long as the reaction is proceeded, it may for example bea solvent such as an ether, hydrocarbon, amide, halogenated hydrocarbon,nitrile, ketone and sulfoxide as well as a mixture thereof.

[0748] The reaction temperature is usually about −20 to about 150° C.,preferably about 0 to about 120° C. The reaction time is usually about 5minutes to about 24 hours, preferably about 10 minutes to about 5 hours.

[0749] Compound (VIII′) is produced by reacting Compound (VI′) withCompound (VII′) wherein R¹⁸ is a hydrocarbon group and hal is a halogen,if desired in the presence of a base.

[0750] Said “hydrocarbon group” may for example be a linear or cyclichydrocarbon group (e.g., C₁₋₆ alkyl (for example, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.),C₃₋₆ cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, etc.), C₆₋₁₄ aryl (for example, phenyl, 1-naphthyl,2-naphthyl, biphenylyl, 2-anthryl, etc.), etc.) and the like.

[0751] The amount of Compound (VII′) is about 1 to about 5 moles,preferably about 1 to about 2 moles per mole of Compound (VI′).

[0752] Said “base” may for example be an inorganic base, basic salt,aromatic amine, tertiary amine, alkaline metal hydride, alkyl metal,aryl metal, metal amide, metal alkoxide and the like. The amount of sucha base employed is about 1 to about 5 moles, preferably about 1 to about2 moles per mole of Compound (VI′).

[0753] This reaction is conducted advantageously using a solvent whichis inert to the reaction. While such a solvent is not limitedparticularly as long as the reaction is proceeded, it may for example bea solvent such as an alcohol, ether, hydrocarbon, amide, halogenatedhydrocarbon, nitrile, sulfoxide, water as well as a mixture thereof.

[0754] The reaction time is usually about 30 minutes to about 48 hours,preferably about 1 hour to about 24 hours. The reaction temperature isusually about −100 to about 200° C., preferably about −80 to about 150°C.

[0755] Compound (VIII′) is produced by reacting Compound (VI′) withCompound (VIIa′) wherein R¹⁹ is an optionally substituted hydrocarbongroup, if desired in the presence of a base.

[0756] Said “hydrocarbon group” may for example be a linear or cyclichydrocarbon group (e.g., C₁₋₆ alkyl (for example, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.),C₃₋₆ cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, etc.), C₆₋₁₄ aryl (for example, phenyl, 1-naphthyl,2-naphthyl, biphenylyl, 2-anthryl), C₇₋₁₆ aralkyl (for example, benzyl,1-naphthylmethyl)) and the like.

[0757] A “substituent” on said “optionally substituted hydrocarbongroup” may for example be a halogen atom (e.g., fluorine, chlorine,bromine, iodine, etc.) and an optionally halogenated C₁₋₆ alkyl, etc.

[0758] The amount of Compound (VIIa′) is about 1 to about 3 moles,preferably about 1 to about 1.5 moles per mole of Compound (VI′).

[0759] Said “base” may for example be an inorganic base, basic salt,aromatic amine, tertiary amine, metal hydride, alkyl metal, aryl metal,metal amide, metal alkoxide and the like. The amount of such a baseemployed is about 1 to about 5 moles, preferably about 1 to about 2moles per mole of Compound (VI′).

[0760] This reaction is conducted advantageously using a solvent whichis inert to the reaction. While such a solvent is not limitedparticularly as long as the reaction is proceeded, it may for example bea solvent such as alcohol, ether, hydrocarbon, amide, halogenatedhydrocarbon, nitrile, sulfoxide, water as well as mixture thereof.

[0761] The reaction time is usually about 30 minutes to about 48 hours,preferably about 1 hour to about 24 hours. The reaction temperature isusually about −100 to about 200° C., preferably about −80 to about 150°C.

[0762] Compound (X′) wherein Z is an optionally substituted hydroxygroup or halogen can be produced by reacting Compound (VI′) and Compound(IX′) wherein M is a metal provided that a salt is included when M ispolyvalent, followed if necessary by an acylation or halogenation.

[0763] Z representing said “optionally substituted hydroxy group” mayfor example be hydroxy, optionally halogenated C₁₋₆ alkylcarbonyloxy(e.g., acetyloxy, trifluoroacetyloxy, propionyloxy, etc.), optionallyhalogenated C₁₋₆ alkylsulfonyloxy (e.g., methanesulfonyloxy,trifluoromethanesulfonyloxy, ethanesulfonyloxy, etc.), optionallysubstituted C₆₋₁₀ arylsulfonyloxy and the like. An “optionallysubstituted C₆₋₁₀ arylsulfonyloxy” may for example, a C₆₋₁₀arylsulfonyloxy (e.g., phenylsulfonyloxy, naphthylsulfonyloxy, etc.)which may have 1 to 3 substituent(s) selected from a halogen, C₁₋₆alkyl, C₁₋₆ alkoxy and nitro, and those exemplified typically arephenylsulfonyloxy, p-chlorophenylsulfonyloxy, m-nitrophenylsulfonyloxy,p-toluenesulfonyloxy and the like.

[0764] Said “metal” may for example be a magnesium halide (e.g.,magnesium bromide, magnesium chloride, etc.), lithium and the like.

[0765] The amount of Compound (IX′) is about 1 to about 3 moles,preferably about 1 to about 1.5 moles per mole of Compound (VI′).

[0766] This reaction may employ additives if desired.

[0767] Said “additives” may for example be cerium (III) chloride, copper(I) iodide and the like. The amount of an additive employed is usuallyabout 0.1 to about 5 moles, preferably about 0.1 to about 2 moles permole of Compound (VI′).

[0768] This reaction is conducted advantageously using a solvent whichis inert to the reaction. While such a solvent is not limitedparticularly as long as the reaction is proceeded, it may for example bea solvent such as an ether and hydrocarbon, as well as a mixturethereof.

[0769] The reaction time is usually about 10 minutes to about 48 hours,preferably about 30 minutes to about 24 hours. The reaction temperatureis usually about −100 to about 150° C., preferably about −80 to about100° C.

[0770] A resultant alcohol form is subjected to an acylation ifnecessary.

[0771] Compound (X′) wherein Z is a hydroxy group and an acylating agentare reacted if desired in the presence of a base or acid.

[0772] Said “acylating agent” may for example be a correspondingcarboxylic acid or a reactive derivative thereof (for example, acidhalide, acid anhydride, ester, etc.), etc. Such an acylating agent isemployed in an amount of about 1 to about 5 moles, preferably about 1 toabout 2 moles per mole of Compound (X′).

[0773] This reaction is conducted advantageously without using a solventor with using a solvent which is inert to the reaction. While such asolvent is not limited particularly as long as the reaction isproceeded, it may for example be a solvent such as an ether,hydrocarbon, amide, halogenated hydrocarbon, nitrile, ketone, sulfoxide,aromatic amine and water as well as a mixture thereof.

[0774] A base employed if desired may for example be an inorganic base,basic salt, aromatic amine, tertiary amine and the like.

[0775] An acid employed if desired may for example be methanesulfonicacid, p-toluenesulfonic acid, camphorsulfonic acid and the like.]

[0776] The reaction temperature is usually about −20 to about 200° C.,preferably about 0 to about 150° C. The reaction time is usually about 5minutes to about 48 hours, preferably about 10 minutes to about 24hours.

[0777] A resultant alcohol form is subjected to a halogenation ifnecessary.

[0778] Compound (X′) wherein Z is a hydroxy group is reacted with ahalogenating agent if desired in the presence of a base.

[0779] Said “halogenating agent” may for example be a thionyl halidesuch as thionyl chloride and thionyl bromide, etc., a phosphoryl halidesuch as phosphoryl chloride and phosphoryl bromide, etc., a phosphorushalide such as phosphorus pentachloride, phosphorus trichloride,phosphorus pentabromide and phosphorus tribromide, etc., an oxalylhalide such as oxalyl chloride, etc., phosgene and the like. Such ahalogenating agent is employed in an amount of about 1 to about 30moles, preferably about 1 to about 10 moles per mole of Compound (X′).

[0780] Said “base” may for example be a tertiary amine.

[0781] This reaction is conducted advantageously without using a solventor with using a solvent which is inert to the reaction. While such asolvent is not limited particularly as long as the reaction isproceeded, it may for example be a solvent such as a hydrocarbon, ether,amide, halogenated hydrocarbon as well as a mixture thereof.

[0782] The reaction time is usually about 10 minutes to about 12 hours,preferably about 10 minutes to about 5 hours. The reaction temperatureis usually about −10 to about 200° C., preferably about −10 to about120° C.

[0783] Compound (I′) wherein Y is CH₂ or CH(OH) and n is 0 is producedby reacting Compound (VIII′) with Compound (XI′) in the presence of anacid or halogenating agent.

[0784] The amount of Compound (XI′) is about 0.5 to about 5 moles,preferably about 0.5 to about 2 moles per mole of Compound (VIII′).Compound (XI′) may be employed also as a solvent, and in such a case theamount used is about 0.5 to about 10 mL, preferably about 1 to about 5mL per gram of Compound (VIII′).

[0785] Said “acid” may for example be a mineral acid such as sulfuricacid, hydrogen chloride, hydrogen bromide, hydrogen iodide andperchloric acid or a Lewis acid such as boron trifluoride diethyl ethercomplex, zinc chloride and aluminum chloride. The amount of an acidemployed is about 1 to about 5 moles, preferably about 1 to about 3moles per mole of Compound (VIII′).

[0786] Said “halogenating agent” may for example be a halogen such asbromine, chlorine and iodine, an imide such as N-bromosuccinimide, ahalogen adduct such as benzyltrimethylammonium dichloroiodate andbenzyltrimethylammonium tribromide and the like. The amount of ahalogenating agent is about 1 to about 5 moles, preferably about 1 toabout 2 moles per mole of Compound (VIII′).

[0787] This reaction is conducted advantageously using a solvent whichis inert to the reaction. While such a solvent is not limitedparticularly as long as the reaction is proceeded, it may for example bea solvent such as a hydrocarbon, organic acid and halogenatedhydrocarbon as well as a mixture thereof.

[0788] The reaction time is usually about 10 minutes to about 48 hours,preferably about 15 minutes to about 24 hours. The reaction temperatureis usually about −20 to about 150° C., preferably about 0 to about 100°C.

[0789] Compound (I′) wherein Y is CH₂ and n is 0 is produced also byreacting Compound (VIII′) with Compound (XII′) in the presence ofphosphoryl chloride.

[0790] The amount of Compound (XII′) employed is about 0.5 to about 5moles, preferably about 0.5 to about 3 moles per mole of Compound(VIII′).

[0791] The amount of phosphoryl chloride employed is about 0.5 to about5 moles, preferably about 0.5 to about 3 moles per mole of Compound(VIII′). Phosphoryl chloride may be employed also as a solvent, and insuch a case the amount used is about 0.5 to about 20 mL, preferablyabout 1 to about 10 mL per gram of Compound (VIII′).

[0792] This reaction is conducted advantageously using a solvent whichis inert to the reaction. While such a solvent is not limitedparticularly as long as the reaction is proceeded, it may for example bea solvent such as a hydrocarbon and halogenated hydrocarbon as well as amixture thereof.

[0793] The reaction time is usually about 10 minutes to about 48 hours,preferably about 15 minutes to about 24 hours. The reaction temperatureis usually about −20 to about 150° C., preferably about 0 to about 100°C.

[0794] Compound (I′) wherein Y is CH₂ or CH(OH) and n is 0 is producedalso from Compound (X′) and Compound (XI′) similarly to the productionof Compound (I′) from Compound (VIII′) and Compound (XI′).

[0795] Compound (I′) is produced also by a process shown in Scheme 2.

[0796] Compound (XIV′), wherein hal is a halogen, is produced byreacting Compound (XIII′) with a halogenating agent.

[0797] Said “halogenating agent” may for example be a halogen such asbromine, chlorine and iodine, etc., an imide such as N-bromosuccinimide,etc., a halogen adduct such as benzyltrimethylammonium dichloroiodateand benzyltrimethylammonium tribromide and the like. The amount of ahalogenating agent is about 1 to about 5 moles, preferably about 1 toabout 2 moles per mole of Compound (XIII′).

[0798] This reaction is conducted advantageously using a solvent whichis inert to the reaction. While such a solvent is not limitedparticularly as long as the reaction is proceeded, it may for example bea solvent such as a hydrocarbon, organic acid and halogenatedhydrocarbon as well as a mixture thereof.

[0799] The reaction time is usually about 10 minutes to about 48 hours,preferably about 15 minutes to about 24 hours. The reaction temperatureis usually about −20 to about 150° C., preferably about 0 to about 100°C.

[0800] The process from Compound (XIV′) to Compound (XVII′) is conductedin accordance with the process for producing Compound (VI′) fromCompound (II′) in Scheme 1.

[0801] Compound (XIX′) is produced by reacting Compound (XVII′) withCompound (XVIII′), wherein R^(3a) is a divalent group formed by removingone hydrogen atom from R³ and Wa is a leaving group, in the presence ofa base.

[0802] The amount of Compound (XVIII′) is about 1 to about 3 moles,preferably about 1 to about 1.5 moles per mole of Compound (XVII′).

[0803] Said “leaving group” may for example be a halogen atom (forexample, fluorine, chlorine, bromine, iodine, etc.), optionallyhalogenated C₁₋₅ alkylsulfonyloxy (for example, methanesulfonyloxy,ethanesulfonyloxy, trichloromethanesulfonyloxy, etc.), optionallysubstituted C₆₋₁₀ arylsulfonyloxy and the like. An “optionallysubstituted C₆₋₁₀ arylsulfonyloxy” may for example, a C₆₋₁₀arylsulfonyloxy (e.g., phenylsulfonyloxy, naphthylsulfonyloxy) which mayhave 1 to 3 substituent(s) selected from a C₁₋₆ alkyl (e.g. methyl,ethyl, etc.), C₁₋₆ alkoxy (e.g., methoxy, ethoxy, etc.) and nitro, andthose exemplified typically are phenylsulfonyloxy,m-nitrophenylsulfonyloxy, p-toluenesulfonyloxy and the like.

[0804] Said “base” may for example be metal amide, alkyl metal, arylmetal and the like. The amount of a base employed is about 1 to about 5moles, preferably about 1 to about 2 moles per mole of Compound (XVII′).

[0805] This reaction may employ additives if desired.

[0806] Said “additives” may for example be cerium (III) chloride, copper(I) iodide and the like. The amount of an additive employed is usuallyabout 0.1 to about 5 moles, preferably about 0.1 to about 2 moles permole of Compound (XVII′).

[0807] This reaction is conducted advantageously using a solvent whichis inert to the reaction. While such a solvent is not limitedparticularly as long as the reaction is proceeded, it may for example bea solvent such as an ether and hydrocarbon, as well as a mixturethereof.

[0808] The reaction time is usually about 10 minutes to about 48 hours,preferably about 30 minutes to about 24 hours. The reaction temperatureis usually about −100 to about 150° C., preferably about −80 to about100° C.

[0809] Compound (I′), wherein Y is CH₂ and n is 0, is produced also fromCompound (XIX′) and Compound (XI′) similarly to the production ofCompound (I′) from Compound (VIII′) and Compound (XI′).

[0810] Compound (I′) is produced also by a process shown in Scheme 3.

[0811] Compound (XXII′) is produced by reacting Compound (VI′) andCompound (XX′), wherein R¹⁹ is an optionally substituted hydrocarbongroup, in the presence of a base.

[0812] Said “hydrocarbon group” may for example be a linear or cyclichydrocarbon group (e.g., C₁₋₆ alkyl (for example, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.),C₃₋₆ cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, etc.), C₆₋₁₄ aryl (for example, phenyl, 1-naphthyl,2-naphthyl, biphenylyl, 2-anthryl, etc.), C₇₋₁₆ aralkyl (for example,benzyl, 1-naphthylmethyl, etc.), etc.) and the like.

[0813] A “substituent” on said “optionally substituted hydrocarbongroup” may for example be a halogen atom (e.g., fluorine, chlorine,bromine, iodine, etc.) and an optionally halogenated C₁₋₆ alkyl, etc.

[0814] The amount of Compound (XX′) is about 1 to about 5 moles,preferably about 1 to about 2 moles per mole of Compound (VI′).

[0815] Said “base” may for example be an alkaline metal hydride, alkylmetal, aryl metal, metal amide and the like. The amount of such a baseemployed is about 1 to about 5 moles, preferably about 1 to about 2moles per mole of Compound (VI′).

[0816] This reaction is conducted advantageously using a solvent whichis inert to the reaction. While such a solvent is not limitedparticularly as long as the reaction is proceeded, it may for example bea solvent such as ether and hydrocarbon as well as a mixture thereof.

[0817] The reaction time is usually about 30 minutes to about 48 hours,preferably about 1 hour to about 24 hours. The reaction temperature isusually about −100 to about 150° C., preferably about −80 to about 100°C.

[0818] Compound (XXII′) is produced by reacting Compound (VI′) withCompound (XXI′), wherein R¹⁹ and hal are defined as described above, inthe presence of zinc.

[0819] The amount of each of Compound (XXI′) and zinc employed is about1 to about 5 moles, preferably about 1 to about 2 moles per mole ofCompound (VI′).

[0820] This reaction is conducted advantageously using a solvent whichis inert to the reaction. While such a solvent is not limitedparticularly as long as the reaction is proceeded, it may for example bea solvent such as ether, hydrocarbon and nitrile as well as a mixturethereof.

[0821] The reaction time is usually about 30 minutes to about 48 hours,preferably about 1 hour to about 24 hours. The reaction temperature isusually about 0 to about 200° C., preferably about 0 to about 150° C.

[0822] Compound (XXIII′) is produced by reducing Compound (XXII′).

[0823] A reducing agent employed in such a reduction may for example bea silane such as triethylsilane, etc., a metal hydride such astributyltin hydride, aluminum hydride and diusobutylaluminum hydride,etc., a metal hydrogen complex such as lithium aluminum hydride andsodium borohydride, etc., a borane complex such as boranetetrahydrofuran complex and borane dimethylsulfide complex, etc., analkylborane such as thexylborane and disiamylborane, etc., diborane,metal such as zinc, aluminum, tin and iron, etc., an alkaline metal suchas sodium and lithium/liquid ammonia (Birch reduction) and the like.

[0824] The amount of a reducing agent is about 1 to about 10 moles,preferably about 1 to about 3 moles per mole of Compound (XXII′) when asilane, metal hydride or metal hydrogen complex is employed, about 1 toabout 10 moles, preferably about 1 to about 5 moles per mole of Compound(XXII′) when a borane complex, alkyl borane or diborane is employed, andabout 1 to about 20 equivalents, preferably about 1 to about 5equivalents when metal or alkaline metal is employed. This reaction mayemploy a Lewis acid if desired. Said “Lewis acids” may for example bealuminum chloride, aluminum bromide, titanium (IV) chloride, tin (II)chloride, zinc chloride, boron trichloride, boron tribromide, borontrifluoride and the like. The amount of a Lewis acid employed is about 1to about 5 moles, preferably about 1 to about 2 moles per mole ofCompound (XXII′).

[0825] A hydrogenation reaction may also serve for the reduction, and insuch a case a catalyst such as Pd/C, platinum (IV) oxide, Raney nickeland Raney cobalt, etc. may be employed. The amount of a catalystemployed is about 5 to about 1000% by weight, preferably about 10 toabout 300% by weight, based on Compound (XXII′).

[0826] This reaction is conducted advantageously using a solvent whichis inert to the reaction. While such a solvent is not limitedparticularly as long as the reaction is proceeded, it may for example besolvent such as alcohol, ether, hydrocarbon, halogenated hydrocarbon,amide and organic acid as well as a mixture thereof.

[0827] The reaction time is usually about 1 hour to about 100 hours,preferably about 1 hour to about 50 hours, although it may varydepending on the type and the amount of the reducing agent employed andthe activity and the amount of the catalyst. The reaction temperature isusually about −20 to about 120° C., preferably about 0 to about 80° C.When a hydrogenation catalyst is employed, the pressure of hydrogen isusually about 1 to about 100 atm.

[0828] Compound (XXIV′) is produced by hydrolyzing the ester group ofCompound (XXIII′) using acid or base.

[0829] The acidic hydrolysis usually employs mineral acid such ashydrochloric acid and sulfuric acid, a Lewis acid such as borontrichloride and boron tribromide, a combination of a Lewis acid and athiol or sulfide, an organic acid such as trifluoroacetic acid andp-toluenesulfonic acid, etc.

[0830] The basic hydrolysis usually employs an inorganic base, basicsalt, metal alkoxide and the like.

[0831] The amount of each of the acid and base employed is about 0.5 toabout 10 moles, preferably about 0.5 to about 5 moles per mole ofCompound (XXIII′).

[0832] This reaction is conducted advantageously using a solvent whichis inert to the reaction. While such a solvent is not limitedparticularly as long as the reaction is proceeded, it may for example bea solvent such as an alcohol, hydrocarbon, organic acid, ether, amide,halogenated hydrocarbon, nitrile, ketone, sulfoxide and water as well asa mixture thereof.

[0833] The reaction time is usually about 10 minutes to about 48 hours,preferably about 15 minutes to about 24 hours. The reaction temperatureis usually about −20 to about 150° C., preferably about 0 to about 100°C.

[0834] Compound (XXV′) is produced by subjecting Compound (XXIV′) to arearrangement directly or after converting into a reactive derivativethereof (for example, acid halide, acid amide, acid anhydride, ester,etc.).

[0835] Said “rearrangement” may for example be a Curtius rearrangement,Hofmann rearrangement, Schmidt rearrangement and the like.

[0836] A case employing diphenylphosphoryl azide is described below.

[0837] The amount of diphenylphosphoryl azide is about 1 to about 3moles, preferably about 1 to about 1.5 moles per mole of Compound(XXIV′).

[0838] This reaction is conducted if desired in the presence of a base.

[0839] Said “base” is preferably tertiary amine, aromatic amine and thelike.

[0840] This reaction is conducted advantageously using a solvent whichis inert to the reaction. While such a solvent is not limitedparticularly as long as the reaction is proceeded, it may for example bea solvent such as a hydrocarbon, halogenated hydrocarbon and ether aswell as a mixture thereof.

[0841] The reaction time is usually about 10 minutes to about 48 hours,preferably about 15 minutes to about 24 hours. The reaction temperatureis usually about −20 to about 200° C., preferably about 0 to about 150°C.

[0842] Other reaction conditions are those described in JIKKENKAGAKUKOZA20, 4th edition (Ed. by Japanese Association of Chemistry), pages 304,477 to 479.

[0843] Compound (XXVI′) is produced by subjecting Compound (XXV′) to theacidic hydrolysis.

[0844] The acidic hydrolysis usually employs a mineral acid such ashydrochloric acid and sulfuric acid, etc., a Lewis acid such as borontrichloride and boron tribromide, etc., a combination of a Lewis acidand a thiol or sulfide, an organic acid such as trifluoroacetic acid andp-toluenesulfonic acid, etc.

[0845] The amount of such an acid employed is about 0.5 to about 10moles, preferably about 0.5 to about 5 moles per mole of Compound(XXV′).

[0846] This reaction is conducted advantageously using a solvent whichis inert to the reaction. While such a solvent is not limitedparticularly as long as the reaction is proceeded, it may for example bea solvent such as a hydrocarbon, ether, halogenated hydrocarbon, ketone,sulfoxide and water as well as a mixture thereof.

[0847] The reaction time is usually about 10 minutes to about 48 hours,preferably about 15 minutes to about 24 hours. The reaction temperatureis usually about −20 to about 200° C., preferably about 0 to about 150°C.

[0848] Compound (XXVIII′) is produced by reacting Compound (XXVI′) andCompound (XXVII′), wherein V is an optionally substituted hydroxy group,halogen and the like, if desired in the presence of a base or acid.

[0849] V, which represents said “optionally substituted hydroxy groups”may for example be a hydroxy, optionally halogenated C₁₋₆alkylcarbonyloxy (e.g., acetyloxy, trifluoroacetyloxy, propionyloxy,etc.), optionally halogenated C₁₋₆ alkylsulfonyloxy (e.g.,methanesulfonyloxy, trifluoromethanesulfonyloxy, ethanesulfonyloxy,etc.), optionally substituted C₆₋₁₀ arylsulfonyloxy, or a grouprepresented by Formula: R¹—CO₂ and the like. An “optionally substitutedC₆₋₁₀ arylsulfonyloxy” may for example, a C₆₋₁₀ arylsulfonyloxy (e.g.,phenylsulfonyloxy, naphthylsulfonyloxy, etc.) which may have 1 to 3substituent(s) selected from a halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy andnitro, and those exemplified typically are phenylsulfonyloxy,p-chlorophenylsulfonyloxy, m-nitrophenylsulfonyloxy,p-toluenesulfonyloxy and the like.

[0850] Compound (XXVII′) is employed in an amount of about 1 to about 5moles, preferably about 1 to about 2 moles per mole of Compound (XXVI′).

[0851] This reaction is conducted advantageously without using a solventor with using a solvent which is inert to the reaction. While such asolvent is not limited particularly as long as the reaction isproceeded, it may for example be a solvent such as ether, hydrocarbon,amide, halogenated hydrocarbon, nitrile, ketone, sulfoxide, aromaticamine and water as well as a mixture thereof.

[0852] A base employed if desired may for example be an inorganic base,basic salt, aromatic amine, tertiary amine and the like.

[0853] An acid employed if desired may for example be methanesulfonicacid, p-toluenesulfonic acid, camphorsulfonic acid and the like.

[0854] The reaction temperature is usually about −20 to about 200° C.,preferably about 0 to about 150° C. The reaction time is usually about 5minutes to about 48 hours, preferably about 10 minutes to about 24hours.

[0855] Compound (XXVIII′) is produced also by reacting Compound (XXV′)and Compound (XXIX′), wherein R^(1d) and R^(1e) are substituents forminga part of R¹ and each is a hydrogen atom or optionally substitutedhydrocarbon group, if desired in the presence of a base or acid.

[0856] Said “hydrocarbon group” may for example be a linear or cyclichydrocarbon group (e.g., C₁₋₆ alkyl (for example, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.),C₃₋₆ cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, etc.), C₆₋₁₄ aryl (for example, phenyl, 1-naphthyl,2-naphthyl, biphenylyl, 2-anthryl, etc.), C₇ ₁₋₆ aralkyl (for example,benzyl, 1-naphthylmethyl, etc.), etc.).and the like.

[0857] The “substituent” on said optionally substituted hydrocarbongroup may for example be a halogen atom (e.g., fluorine, chlorine,bromine, iodine, etc.) and an optionally halogenated C₁₋₆ alkyl, etc.

[0858] The amount of Compound. (XXIX′) is about 1 to about 3 moles,preferably about 1 to about 2 moles per mole of Compound (XXV′).

[0859] This reaction is conducted advantageously using a solvent whichis inert to the reaction. While such a solvent is not limitedparticularly as long as the reaction is proceeded, it may for example bea solvent such as an ether, hydrocarbon, amide, halogenated hydrocarbon,nitrile and sulfoxide as well as a mixture thereof.

[0860] The reaction time is usually about 30 minutes to about 48 hours,preferably about 1 hour to about 24 hours. The reaction temperature isusually about −20 to about 150° C., preferably about 0 to about 100° C.

[0861] Compound (I′), wherein Y is CH₂ and n is 0, is produced bysubjecting Compound (XXVIII′) to an intramolecular cyclization using ahalogenating agent and the like.

[0862] Said “halogenating agent” may for example be phosphoryl chloride,phosphorus pentachloride, phosphorus pentoxide, aluminum chloride andthe like.

[0863] The amount of said “halogenating agent” is about 1 to about 20moles, preferably about 1 mole to about 5 moles per mole of Compound(XXVIII′). Said “halogenating agent” may be used also as a solvent, andin such a case the amount used is about 0.5 to about 20 mL, preferablyabout 1 to about 10 mL pert gram of Compound (XXVIII′).

[0864] This reaction is conducted advantageously using a solvent whichis inert to the reaction. While such a solvent is not limitedparticularly as long as the reaction is proceeded, it may for example bea solvent such as a hydrocarbon, nitrile and halogenated hydrocarbon aswell as a mixture thereof.

[0865] The reaction temperature is usually about −20 to about 200° C,preferably about 0 to about 150° C. The reaction time is usually about 5minutes to about 48 hours, preferably about 10 minutes to about 24hours.

[0866] Compound (I′) is produced also by a process shown in Scheme 4.

[0867] Compound (XXX′) is produced by reducing Compound (I′) wherein nis 0.

[0868] The reducing agent employed in such a reduction may for examplebe a metal hydride such as tributyltin hydride, aluminum hydride anddiisobutylaluminum hydride, etc., a metal hydrogen complex such aslithium aluminum hydride and sodium borohydride, etc., a borane complexsuch as borane tetrahydrofuran complex and borane dimethylsulfidecomplex, an alkylborane such as thexylborane and disiamylborane, etc.,diborane, a metal such as zinc, aluminum, tin and iron, etc., analkaline metal such as sodium and lithium/liquid ammonia (Birchreduction) and the like.

[0869] The amount of a reducing agent is about 1 to about 10 preferablyabout 1 to about 3 moles per mole of Compound when a silane, metalhydride o metal hydrogen complex is employed, about 1 to about 10 moles,preferably about 1 to about 5 moles per mole of Compound (I′) when aborane complex, alkyl borane or diborane is employed, and about 1 toabout 20 equivalents, preferably about 1 to about 5 equivalents when ametal or alkaline metal 5 employed. This reaction may employ a Lewisacid if desired. Said “Lewis acid” may for example be aluminum chloride,aluminum bromide, titanium (IV) chloride, tin (II) chloride zincchloride, boron trichloride, boron tribromide, boron trifluoride and thelike. The amount of a Lewis acid employed is about 1 to about 5 moles,preferably about 1 to about 2 moles per mole of Compound (I′).

[0870] A hydrogenation reaction may also serve for the reduction, and insuch a case a catalyst such as Pd/C, platinum (IV) oxide, Raney nickeland Raney cobalt may be employed. The amount of a catalyst employed isabout 5 to about 1000% by weight, preferably about 10 to about 300% byweight, based on Compound (I′).

[0871] This reaction is conducted advantageously using a solvent whichis inert to the reaction. While such a solvent is not limitedparticularly as long as the reaction is proceeded, it may for example bea solvent such as an alcohol, ether, hydrocarbon, amide and organic acidas well as a mixture thereof.

[0872] The reaction time is usually about 1 hour to about 100 hours,preferably about 1 hour to about 50 hours, although it may varydepending on the type and the amount of the reducing agent employed andthe activity and the amount of the catalyst. The reaction temperature isusually about −20 to about 120° C., preferably about 0 to about 80° C.When a hydrogenation catalyst is employed, the pressure of hydrogen isusually about 1 to about 100 atm.

[0873] Compound (I′) wherein n is 1 is produced by oxidizing Compound(XXX′).

[0874] An oxidizing agent employed in such an oxidation may for examplebe hydrogen peroxide, etc. The amount of an oxidizing agent employed isabout 1 to about 20 moles, preferably about 1 to about 5 moles per moleof Compound (XXX′),

[0875] In this reaction, it is preferable to use a catalyst such assodium tungstate (VI). The amount of such a catalyst is about 0.05 toabout 1 moles, preferably about 0.05 to about 0.5 moles per mole ofCompound (XXX′).

[0876] This reaction is conducted advantageously using a solvent whichis inert to the reaction. While such a solvent is not limitedparticularly as long as the reaction is proceeded, it may for example bea solvent such as an alcohol, hydrocarbon, amide, halogenatedhydrocarbon and water as well as a mixture thereof.

[0877] The reaction time is usually about 30 minutes to about 48 hours,preferably about 1 hour to about 24 hours. The reaction temperature isusually about −20 to about 150° C., preferably about 0 to about 100° C.

[0878] Compound (XXXII′) is produced from Compound (XIII′) and Compound(XXXI′), wherein R¹⁶, R¹⁷ and W are defined as described above,similarly to the production of Compound (IV′) from Compound (II′) andCompound (III′).

[0879] Compound (XXXIV′) is produced from Compound (XXXII′) and Compound(XXXIII′), wherein R¹⁸ and hal are defined as described above, similarlyto the production of Compound (VIII′) from Compound (VI′) and Compound(VII′).

[0880] Compound (XXXIV′) is also produced from Compound (XXXII′) andCompound (XXXIIIa′), wherein R¹⁹ is defined as described above,similarly to the production of Compound (VIII′) from Compound (VI′) andCompound (VIIa′).

[0881] Compound (XXXIV′) is also produced from Compound (XIII′) andCompound (III′) similarly to the production of Compound (IV′) fromCompound (II′) and Compound (III′).

[0882] The process from Compound (XXXIV′) to Compound (XXXVI′) isconducted in accordance with the process for producing Compound (VI′)from Compound (IV′) in Scheme 1.

[0883] Compound (VI′) is produced by reacting Compound (XXXVI′) with aformamide in the presence of an acid catalyst.

[0884] Said “formamide” may for example be dimethylformamide andN-methylformanilide, etc. The formamide is used in an amount of about 1to about 10 moles, preferably about 1 to about 5 moles per mole ofCompound (XXXVI′).

[0885] Said “acid catalysts” may for example be phosphoryl chloride andthionyl chloride. Such an acid catalyst is employed usually in an amountof about 1 to about 10 moles, preferably about 1 to about 5 moles permole of Compound (XXXVI′).

[0886] This reaction is conducted advantageously using a solvent whichis inert to the reaction. While such a solvent is not limitedparticularly as long as the reaction is proceeded, it may for example bea solvent such as an amide, ether, hydrocarbon, halogenated hydrocarbonand nitrile as well as a mixture thereof.

[0887] The reaction time is usually about 10 minutes to about 48 hours,preferably about 30 minutes to about 24 hours. The reaction temperatureis usually about −20 to about 150° C., preferably about 0 to about 100°C.

[0888] Compound (VI′) is produced also by reacting Compound (XXXVI′)with a dichloromethylalkyl ether in the presence of an acid catalyst.

[0889] Said “dichloromethylalkyl ether” may for example bedichloromethylmethyl ether and dichloromethylbutyl ether, etc. Thedichloromethylalkyl-ether is used in an amount of about 1 to 5 moles,preferably about 1 to 3 moles per mole of Compound (XXXVI′).

[0890] Said “acid catalyst” may for example be titanium (IV) chloride,aluminum chloride or tin (IV) chloride. An acid catalyst is used in anamount of about 1 to 5 moles, preferably about 1 to 3 moles per mole ofCompound (XXXVI′).

[0891] This reaction is conducted advantageously using a solvent whichis inert to the reaction. While such a solvent is not limitedparticularly as long as the reaction is proceeded, it may for example bea solvent such as an ether, hydrocarbon, halogenated hydrocarbon andnitrile as well as a mixture thereof.

[0892] The reaction time is usually about 10 minutes to about 48 hours,preferably about 30 minutes to about 24 hours. The reaction temperatureis usually about −20 to about 100° C., preferably about 0 to about 80°C.

[0893] Compound (XXXIX′) is produced by reacting Compound (XXXVII′)wherein hal is a halogen with Compound (XXXVIII′) wherein R^(8a) is adivalent group formed by removing one hydrogen atom from R⁸ and W isdefined as described above similarly to the production of Compound (IV′)from Compound (II′) and Compound (III′).

[0894] Compound (VI′) is produced by subjecting Compound (XXXIX′) to aring closure in the presence of a catalyst or in the presence of aradical initiator.

[0895] In a case of a ring closure using a catalyst, said catalyst mayfor example be a palladium such as palladium (II) acetate and palladium(II) chloride, etc. The amount of a catalyst employed is about 0.01 toabout 0.5 mole, preferably about 0.01 to about 0.2 moles per mole ofCompound (XXXIX′).

[0896] This reaction preferably employs additives. Said “additives” mayfor example be a quaternary ammonium salt such as tetrabutylammoniumchloride, etc., tetramethylammonium chloride and tetraethylammoniumchloride, a metal halide such as lithium chloride, etc.,triphenylphosphine and the like. The amount of additives employed isusually about 1 to about 5 moles, preferably about 1 to about 2 molesper mole of Compound (XXXIX′).

[0897] This reaction preferably employs a base if desired. Said “base”may for example be an inorganic base, basic salt, aromatic amine,tertiary amine, metal alkoxide and the like. The amount of such a baseemployed is about 1 to about 5 moles, preferably about 1 to about 2moles per mole of Compound (XXXIX′).

[0898] In addition, it is preferable to add a formate such as sodiumformate in this reaction. The amount of such a formate employed is about1 to about 5 moles, preferably about 1 to about 2 moles per mole ofCompound (XXXIX′).

[0899] This reaction is conducted advantageously using a solvent whichis inert to the reaction. While such a solvent is not limitedparticularly as long as the reaction is proceeded, it may for example bea solvent such as an alcohol, ether, hydrocarbon, amide and ketone aswell as a mixture thereof.

[0900] The reaction time is usually about 10 minutes to about 48 hours,preferably about 30 minutes to about 24 hours. The reaction temperatureis usually about 0 to about 150° C., preferably about 0 to about 120° C.

[0901] In a case of a ring closure using a radical initiator, said“radical initiator” may for example be benzoyl peroxide,2,2′-azobis(isobutyronitrile) and the like. The amount of a radicalinitiator employed is about 0.01 to about 1 moles, preferably about0.0.1 to about 0.1 moles per mole of Compound (XXXIX′).

[0902] This reaction employs a radical source and the like. Said“radical source” may for example be hypophosphorous acid,tris(trimethylsilyl)silane, tributyltin hydride and the like. The amountof a radical source employed is about 1 to about 100 moles, preferablyabout 1 to about 50 moles per mole of Compound (XXXIX′).

[0903] This reaction preferably employs a base if desired. Said “base”may for example be inorganic base, basic salt, aromatic amine, tertiaryamine, metal alkoxide and the like. The amount of such a base employedis about 1 to about 5 moles, preferably about 1 to about 2 moles permole of Compound (XXXIX′).

[0904] This reaction is conducted advantageously using a solvent whichis inert to the reaction. While such a solvent is not limitedparticularly as long as the reaction is proceeded, it may for example bea solvent such as an alcohol, ether, hydrocarbon, amide and ketone aswell as a mixture thereof.

[0905] The reaction time is usually about 10 minutes to about 48 hours,preferably about 30 minutes to about 24 hours. The reaction temperatureis usually about 0 to about 200° C. preferably about 0 to about 150° C.

[0906] Compound (XLII′) is produced by reacting Compound (XL′) withCompound (XLI′), wherein R¹⁹ and W is defined as described above,similarly to the production of Compound (IV′) from Compound (II′) andCompound (III′).

[0907] Compound (XLIII′) is produced by subjecting Compound (XLII′) to aring closure in the presence of a base. Said “base” may for example bean inorganic salt. The amount of a base employed is about 1 to about 10moles, preferably about 1 to about 5 moles per mole of Compound (XLII′).

[0908] This reaction is conducted advantageously using a solvent whichis inert to the reaction. While such a solvent is not limitedparticularly as long as the reaction is proceeded, it may for example bea solvent such as an alcohol, ether, hydrocarbon and water as well as amixture thereof.

[0909] The reaction time is usually about 10 minutes to about 48 hours,preferably about 30 minutes to about 24 hours. The reaction temperatureis usually about 0 to about 150° C., preferably about 0 to about 120° C.

[0910] Compound (XLIV′) is produced by subjecting Compound (XLIII′) to adecarboxylation in the presence of copper.

[0911] The amount of copper employed is about 0.1 to about 5 moles,preferably about 0.5 to about 3 moles per mole of Compound (XLIII′).

[0912] This reaction is conducted advantageously using a solvent whichis inert to the reaction. While such a solvent is not limitedparticularly as long as the reaction is proceeded, it may for example bea solvent such as a hydrocarbon including tetrahydronaphthalene, etc.,ether including diphenyl ether, etc., aromatic amine includingquinoline, etc. and a tertiary amine including N,N-diethylaniline, etc.as well as a mixture thereof.

[0913] The reaction time is usually about 10 minutes to about 24 hours,preferably about 15 minutes to about 12 hours. The reaction temperatureis usually about 100 to about 300° C., preferably about 100 to about250° C.

[0914] Compound (XXXVIa′) is produced by subjecting Compound (XLIV′) toa hydrogenation. In this reaction, a hydrogenation catalyst such asPd/C, platinum (IV) oxide, Raney nickel and Raney cobalt, etc. may beemployed. The amount of the catalyst employed is about 5 to about 1000%by weight, preferably about 10 to about 300% by weight, based onCompound (XLIV′).

[0915] This reaction is conducted advantageously using a solvent whichis inert to the reaction. While such a solvent is not limitedparticularly as long as the reaction is proceeded, it may for example bea solvent such as alcohol, ether, hydrocarbon, amide and organic acid aswell as a mixture thereof.

[0916] The reaction time is usually about 1 hour to about 100 hours,preferably about 1 hour to about 50 hours, although it may varydepending on the activity and the amount of the catalyst employed. Thereaction temperature is usually about −20 to about 120° C., preferablyabout 0 to, about 80° C. The pressure of hydrogen is usually about 1 toabout 100 atm.

[0917] Compound (VIa′) is produced from Compound (XXXVIa′) similarly tothe production of Compound (VI′) from Compound (XXXVI′).

[0918] Compound (XLV′) is produced from Compound (VI′) similarly to theproduction of Compound (XXX′) from Compound (I′).

[0919] Compound (XLVI′), wherein R¹⁸ and hal are defined as describedabove, is produced by halogenating Compound (XLV′) followed by areaction with a corresponding phosphine.

[0920] The halogenating agent employed in such a halogenation may forexample be thionyl halide such as thionyl chloride and thionyl bromide,etc., a phosphoryl halide such as phosphoryl chloride and phosphorylbromide, etc., a phosphorus halide such as phosphorus pentachloride,phosphorus trichloride, phosphorus pentabromide and phosphorustribromide, etc., an oxalyl halide such as oxalyl chloride, etc.,phosgene and the like. Such a halogenating agent is employed in anamount of about 0.1 to about 30 moles, preferably about 0.2 to about 10moles per mole of Compound (XLV′).

[0921] This reaction is conducted if desired in the presence of a base.Said “base” is preferably a tertiary amine, and the like.

[0922] This reaction is conducted advantageously without using a solventor with using a solvent which is inert to the reaction. While such asolvent is not limited particularly as long as the reaction isproceeded, it may for example be a solvent such as a hydrocarbon, ether,amide and halogenated hydrocarbon as well as a mixture thereof.

[0923] The reaction time is usually about 10 minutes to about 12 hours,preferably about 10 minutes to about 5 hours. The reaction temperatureis usually about −10 to about 200° C., preferably about −10 to about120° C.

[0924] The phosphine employed in the subsequent reaction with 20 thephosphine may for example be triphenylphosphine, tri-o-tolylphosphine,tributylphosphine and the like. The phosphine is employed in an amountof about 1 to about 3 moles, preferably about 1 to about 1.5 moles permole of Compound (XLV′).

[0925] This reaction is conducted advantageously without using a solventor with using a solvent which is inert to the reaction. While such asolvent is not limited particularly as long as the reaction isproceeded, it may for example be a solvent such as an ether,hydrocarbon, halogenated-hydrocarbon and nitrile as well as a mixturethereof.

[0926] The reaction temperature is usually about −20 to about 200° C.,preferably about 0 to about 150° C. The reaction time is usually about 5minutes to about 48 hours, preferably about 10 minutes to about 24hours.

[0927] Compound (VIII′) is also produced from Compound (XLVI′) andCompound (XLVII′) similarly to the production of Compound (VIII′) fromCompound (VI′) and Compound (VII′).

[0928] Compound (VIII′) is also produced by a process shown in Scheme 9.

[0929] The process from Compound (XXXV′) to Compound (VIII′), whereinR^(3a) and W are defined as described above, is conducted in accordancewith the process for producing Compound (VI′) from Compound (II′) inScheme 1.

[0930] Compound (VIc′), wherein hal is a halogen, is produced fromCompound (VIb′) similarly to the production of Compound (XIV′) fromCompound (VIb′).

[0931] Compound (VIIIa′) is produced from Compound (VIc′) and Compound(VII′), wherein R¹⁸ and hal are defined as described above, similarly tothe production of Compound (VIII′) from Compound (VI′) and Compound(VII′).

[0932] Compound (VIIIa′) is produced from Compound (VIc′), and Compound(VIIa′), wherein R¹⁹ is defined as described above, similarly to theproduction of Compound (VIII′) from Compound (VI′) and Compound (VIIa′).

[0933] Compound (VIII′), wherein X is a sulfur atom, is produced byreacting Compound (VIIIa′) with a disulfide compound (L′) in thepresence of a base. The amount of Compound (L′) employed is about 1 toabout 30 moles, preferably about 1 to about 15 moles per mole ofCompound (VIIIa′).

[0934] Said “base” may for example be an alkyl metal, aryl metal and thelike.

[0935] The amount of a base employed is about 1 to about 15 moles,preferably about 1 to about 10 moles per mole of Compound (VIIIa′).

[0936] This reaction employs additives if desired.

[0937] Such “additives” may for example beN,N,N′,N′-tetramethylethylenediamine and the like. The amount ofadditives is about 1 to about 15 moles, preferably about 1 to about 10moles per mole of Compound (VIIIa′).

[0938] This reaction is conducted advantageously using a solvent whichis inert to the reaction. While such a solvent is not limitedparticularly as long as the reaction is proceeded, it may for example bea solvent such as an ether and hydrocarbon as well as a mixture thereof.

[0939] The reaction time is usually about 30 minutes to about 48 hours,preferably about 1 hour to about 24 hours. The reaction temperature isusually about −100 to about 100° C., preferably about −80 to about 60°C.

[0940] Compound (LII′) is produced by reacting Compound (VI′) andCompound (LI′) if desired in the presence of a base.

[0941] The amount of Compound (LI′) employed is about 1 to about 5moles, preferably about 1 to about 2 moles per mole of Compound (VI′).Compound (LI′) may be also employed as a solvent, and in such a case theamount used is about 0.5 to about 20 mL, preferably about 1 to about 10mL per gram of Compound (VI′).

[0942] Said “base” may for example be an inorganic base, basic salt,aromatic amine, primary amine (n-butylamine, etc.), tertiary amine,metal hydride, metal amide and metal alkoxide, etc. The amount of a baseemployed is about 0.1 to about 10 moles, preferably about 0.5 to about 5moles per mole of Compound (VI′).

[0943] This reaction is conducted advantageously using a solvent whichis inert to the reaction. While such a solvent is not limitedparticularly as long as the reaction is proceeded, it may for example bea solvent such as an alcohol, ether, hydrocarbon, amide, halogenatedhydrocarbon and water as well as a mixture thereof.

[0944] The reaction time is usually about 30 minutes to about 12 hours,preferably about 1 hour to about 6 hours. The reaction temperature isusually about −20 to about 200° C. preferably about 0 to about 150° C.

[0945] Compound (XXVIa′) is produced by reducing Compound (LII′). Thereducing agent employed in such a reduction may for example be metalhydride such as aluminum hydride and diisobutylaluminum-hydride, etc.,metal hydrogen complex such as lithium aluminum hydride and sodiumborohydride, etc., a metal such as zinc, aluminum, tin and iron, etc.The amount of the reducing agent employed is about 1 to about 10 moles,preferably about 1 to about 5 moles per mole of Compound (LII′) when ametal hydride or metal hydrogen complex is employed, while it was about1 to about 20 equivalents, preferably about 1 to about 5 equivalentswhen a metal is employed. In this reaction, a Lewis acid may be employedif desired. Said “Lewis acids” may for example be aluminum chloride,aluminum bromide, titanium (IV) chloride, tin (II) chloride, zincchloride, boron trichloride, boron tribromide, boron trifluoride and thelike. The amount of a Lewis acid employed is about 1 to about 10 moles,preferably about 1 to about 5 moles per mole of Compound (LII′).

[0946] A hydrogenation reaction may also serve for the reduction, and insuch a case the catalyst such as Pd/C, platinum (IV) oxide, Raney nickeland Raney cobalt, etc. may be employed. The amount of the catalystemployed is about 5 to about 1000% by weight, preferably about 10 toabout 300% by weight, based on Compound (LII′). In such a case, varioushydrogen sources may be employed instead of gaseous hydrogen.

[0947] Said “hydrogen source” may for example be formic acid, ammoniumformate, triethylammonium formate, sodium phosphinate, hydrazine and thelike. The amount of such a hydrogen source is about 1 to about 10 moles,preferably about 1 to about 5 moles, per mole of Compound (LII′).

[0948] This reaction is conducted advantageously using a solvent whichis inert to the reaction. While such a solvent is not limitedparticularly as long as the reaction is proceeded, it may for example bea solvent such as an alcohol, ether, hydrocarbon, amide and organic acidas well as a mixture thereof.

[0949] The reaction time is usually about 1 hour to about 100 hours,preferably about 1 hour to about 50 hours, although it may varydepending on the type and the amount of the reducing agent employed andthe activity and the amount of the catalyst. The reaction temperature isusually about −20 to about 120° C., preferably about 0 to about 80° C.When a hydrogenation catalyst is employed, the pressure of hydrogen isusually about 1 to about 100 atm.

[0950] Compound (Ia), wherein Ring C″ may have a substituent other thanR¹, R² and R³, is produced by a process shown in Scheme 12.

[0951] Compound (LIV) is produced from Compound (LIII) and Compound(VII′), wherein R¹⁸ and hal are defined as described above, similarly tothe production of Compound (VIII′) from Compound (VI′) and Compound(VII′).

[0952] Compound (LIV) is also produced from Compound (LIII) and Compound(VIIa′), wherein R¹⁹ is defined as described above, similarly to theproduction of Compound(VIII′) from Compound (VI′) and Compound (VIIa′).

[0953] Compound (LV), wherein Z is defined as described above, isproduced from Compound (LIII) and Compound (IX′), wherein M is definedas described above, similarly to the production of Compound(X′) fromCompound (VI′) and Compound (IX′).

[0954] Compound (Ia) is produced from Compound (LIV) and Compound (XI′)similarly to the production of Compound (I′) from Compound (VIII′) andCompound (XI′).

[0955] Compound (Ia) is also produced from Compound (LIV) and Compound(XII′) similarly to the production of Compound (I′) from Compound(VIII′) and Compound,(XII′).

[0956] Compound (Ia) is also produced from Compound (LV) and Compound(XI′) similarly to the production of Compound (I′) from Compound (X′)and Compound (XI′).

[0957] Compound (Ia′), wherein Ring C″ is defined as described above, isalso produced by the process shown in Scheme 13.

[0958] Compound (LVII) is produced from Compound (LVI), wherein hal is ahalogen, and Compound (XVIII′), wherein R^(3a) and Wa are defined asdescribed above, similarly to the production of Compound (XIX′) fromCompound (XVII′) and Compound (XVIII′).

[0959] Compound (Ia) is also produced from Compound (LVII) and Compound(XI′) similarly to the production of Compound (I′) from Compound (XIX′)and Compound (XI′).

[0960] Compound (Ia), wherein Ring C″ is defined as described above, isalso produced by a process shown in Scheme 14.

[0961] Compound (LIX), wherein Y is a methylene group which may have 1or 2 substituent(s) is produced from Compound (LVIII) similarly to theproduction of Compound (XXV′) from Compound (XXIV′).

[0962] The “substituent” on said “methylene group which may havesubstituent(s)” may for example be a C₁₋₆ alkyl group.

[0963] Compound (LX) is produced from Compound (LIX) similarly to theproduction of Compound (XXVI′) from Compound (XXV′).

[0964] Compound (LXI) is produced from Compound (LX) and Compound(XXVII′), wherein V is defined as described above, similarly to theproduction of Compound (XXVIII′) from Compound (XXVI′) and Compound(XXVII′).

[0965] Compound (LXI) is also produced from Compound (LIX) and Compound(XXIX′), wherein R^(1d) and R^(1e) are defined as described above,similarly to the production of Compound (XXVIII′) from Compound (XXV′)and Compound (XXIX′).

[0966] Compound (Ic) wherein Ring C^(a) may have a substituent in theposition except for a nitrogen atom is produced also by a process shownin Scheme 15.

[0967] Compound (LXII) is produced from Compound (Ib), wherein RingC^(a) is defined as described above, similarly to the production ofCompound (XXX′) from Compound (I′).

[0968] Compound (Ic) is produced from Compound (LXII) similarly to theproduction of Compound (I′) from Compound (XXX′).

[0969] Compound (Ia) is also produced from Compound (LXI) similarly tothe production of Compound (I′) from Compound (XXVIII′).

[0970] Compound (LXIV′) is produced by reacting Compound (VI′) andCompound (LXIII′) in the presence of an acid anhydride and a base.

[0971] The amount of Compound (LXIII′) is about 1 to about 5 moles,preferably about 1 to about 2 moles per mole of Compound (VI′).

[0972] Said “acid anhydride” may for example be acetic anhydride and thelike. The amount of such an acid anhydride is about 1 to about 20 moles,preferably about 1 to about 10 moles per mole of Compound (VI′).

[0973] Said “base” may for example be inorganic base, basic salt,aromatic amine, tertiary amine, potassium fluoride/alumina and the like.The amount of the base employed is about 1 to about 5 moles, preferablyabout 1 to about 2 moles per mole of Compound (VI′).

[0974] This reaction is conducted advantageously without using a solventor using a solvent which is inert to the reaction. While such a solventis not limited particularly as long as the reaction is proceeded, it mayfor example be a solvent such a hydrocarbon and halogenated hydrocarbonas well as a mixture thereof.

[0975] The reaction time is usually about 10 minutes to about 12 hours,preferably about 15 minutes to about 6 hours. The reaction temperatureis usually about −20 to about 150° C., preferably about 0 to about 120°C.

[0976] Compound (LXVI′) is produced by reacting Compound (LXIV′) andCompound (LXV′), wherein R¹⁹ is defined as described above, in thepresence of a base.

[0977] The amount of Compound (LXV′) is about 1 to about 10 moles,preferably about 1 to about 5 moles per mole of Compound (LXIV′).Compound (LXV′) may be employed also as a solvent, and in such a casethe amount used is about 0.5 to about 50 mL, preferably about 1 to about20 mL per gram of Compound (LXIV′).

[0978] Said “base” may for example be an inorganic base, basic salt,aromatic amine, tertiary amine and the like. The amount of such a baseemployed is about 0.01 to about 1 mole, preferably about 0.01 to about0.1 moles per mole of Compound (LXIV′).

[0979] This reaction is conducted advantageously without using a solventor with using a solvent which is inert to the reaction. While such asolvent is not limited particularly as long as the reaction isproceeded, it may for example be a solvent such as an alcohol, ether,hydrocarbon, amide, halogenated hydrocarbon, nitrile, ketone andsulfoxide as well as a mixture thereof.

[0980] The reaction time is usually about 10 minutes to about 12 hours,preferably about 15 minutes to about 6 hours. The reaction temperatureis usually about −20 to about 150° C., preferably about 0 to about 100°C.

[0981] Compound (XXVIIIa′), wherein R^(2a) is an optionally substitutedhydrocarbon group or acyl group and may be same to those represented byR², is produced by reducing Compound (LXVI′).

[0982] A reducing agent employed in such a reduction may for example bea metal hydride such as aluminum hydride and diisobutylaluminum hydride,etc., a metal hydrogen complex such as lithium aluminum hydride andsodium borohydride, etc., a metal such as zinc, aluminum, tin and iron,etc. The amount of a reducing agent employed is about 1 to about 10moles, preferably about 1 to about 5 moles per mole of Compound (LXVI′)when a metal hydride or metal hydrogen complex is employed, while it wasabout 1 to about 20 equivalents, preferably about 1 to about 5equivalents when a metal is employed. In this reaction, a Lewis acid maybe employed if desired. Said “Lewis acid” may for example be aluminumchloride, aluminum bromide, titanium (IV) chloride, tin (II) chloride,zinc chloride, boron trichloride, boron tribromide, boron trifluorideand the like. The amount of a Lewis acid employed is about 1 to about 10moles, preferably about 1 to about 5 moles per mole of Compound (LXVI′).

[0983] A hydrogenation reaction may also serve for the reduction, and insuch a case a catalyst such as Pd/C, platinum (IV) oxide, Raney nickeland Raney cobalt may be employed. The amount of a catalyst employed isabout 5 to about 1000% by weight, preferably about 10 to about 300% byweight, based on Compound (LXVI′). In such a case, various hydrogensources may be employed instead of gaseous hydrogen. Said “hydrogensource” may for example be formic acid, ammonium formate,triethylammonium formate, sodium phosphinate, hydrazine and the like.The amount of such a hydrogen source is about 1 to about 10 moles,preferably about 1 to about 5 moles, per mole of Compound (LXVI′).

[0984] This reaction is conducted advantageously using a solvent whichis inert to the reaction. While such a solvent is not limitedparticularly as long as the reaction is proceeded, it may for example besolvent such as alcohol, ether, hydrocarbon, amide and organic acid aswell as a mixture thereof.

[0985] The reaction time is usually about 1 hour to about 100 hours,preferably about 1 hour to about 50 hours, although it may varydepending on the type and the amount of the reducing agent employed andthe activity and the amount of the catalyst. The reaction temperature isusually about −20 to about 120° C., preferably about 0 to about 80° C.When a hydrogenation catalyst is employed, the pressure of hydrogen isusually about 1 to about 100 atm.

[0986] Compound (LXVIII′) is produced by reacting Compound (VI′) andCompound (LXVII′) in the presence of a base followed by a reaction withalcohol.

[0987] The amount of Compound (LXVII′) employed is about 1 to about 5moles, preferably about 1 to about 2 moles per mole of Compound (VI′).

[0988] Said “base” may for example be an inorganic base, basic. salt,aromatic amine, tertiary amine, metal hydride, metal amide and metalalkoxide, etc. The amount of a base employed is about 1 to about 5moles, preferably about 1 to about 3 moles per mole of Compound (VI′).

[0989] This reaction is conducted advantageously using a solvent whichis inert to the reaction. While such a solvent is not limitedparticularly as long as the reaction is proceeded, it may for example bea solvent such as ether, hydrocarbon, amide, halogenated hydrocarbon,nitrile and sulfoxide as well as a mixture thereof.

[0990] The reaction time is usually about 10 minutes to about 6 hours,preferably about 15 minutes to about 3 hours. The reaction temperatureis usually about −100 to about 50° C., preferably about −80 to about 50°C.

[0991] The amount of an alcohol employed subsequently is about 1 toabout 30 mL, preferably about 2 to about 20 mL per gram of Compound(VI′).

[0992] The reaction time is usually about 10 minutes to about 12 hours,preferably about 15 minutes to about 6 hours. The reaction temperatureis usually about −100 to about 150° C., preferably about −80 to about100° C.

[0993] Compound (LXIX′), wherein Y′ is a methylene group having 1 or 2substituent(s) is produced by alkylating Compound (LXVIII′) in thepresence of a base.

[0994] The “substituent” on said “methylene group which hassubstituents” may for example be a C₁₋₆ alkyl group, etc.

[0995] Said “base” may for example be an inorganic base, basic salt,aromatic amine, tertiary amine, metal hydride, metal amide, and metalalkoxide, etc. The amount of a base employed is about 1 to about 5moles, preferably about 1 to about 3 moles per mole of Compound(LXVII′).

[0996] An alkylating agent may for example be a hydrocarbon having aleaving group.

[0997] Said “leaving group” may for example be a halogen atom (forexample, fluorine, chlorine, bromine, iodine, etc.), optionallyhalogenated C₁₋₅ alkylsulfonyloxy (for example, methanesulfonyloxy,ethanesulfonyloxy, trichloromethanesulfonyloxy, etc.), optionallysubstituted C₆₋₁₀ arylsulfonyloxy and the like. An “optionallysubstituted C₆₋₁₀ arylsulfonyloxy” may for example, a C₆₋₁₀arylsulfonyloxy (e.g., phenylsulfonyloxy, naphthylsulfonyloxy, etc.)which may have 1 to 3 substituent(s) selected from a C₁₋₆ alkyl (e.g.methyl, ethyl, etc.), C₁₋₆ alkoxy (e.g., methoxy, ethoxy, etc.) andnitro, and those exemplified typically are phenylsulfonyloxy,m-nitrophenylsulfonyloxy, p-toluenesulfonyloxy and the like.

[0998] Said hydrocarbon may for example be a C₁₋₆ alkyl group, etc.

[0999] The amount of an alkylating agent employed in this reaction isabout 1 to about 10 moles, preferably about 1 to about 3-moles per moleof Compound (LXVIII′).

[1000] This reaction is conducted advantageously using a solvent whichis inert to the reaction. While such a solvent is not limitedparticularly as long as the reaction is proceeded, it may for example bea solvent such as alcohol, ether, hydrocarbon, amide, halogenatedhydrocarbon, nitrile, sulfoxide and water as well as a mixture thereof.

[1001] The reaction time is usually about 30 minutes to about 12 hours,preferably about 1 hour to about 6 hours. The reaction temperature isusually about −50 to about 150° C., preferably about −20 to about 100°C.

[1002] Compound (XXVIb′), wherein Y is a methylene which may have 1 or 2substituent(s), is produced by hydrolyzing the nitrile of Compound(LXIX′) to form an acid amide followed by a reduction.

[1003] The “substituent” on said “methylene group which may havesubstituents” may for example be a C₁₋₆ alkyl group.

[1004] Said “hydrolyzing” reaction is conducted using a base in thepresence of hydrogen peroxide. The amount of hydrogen peroxide employedis about 1 to about 5 mole, preferably about 1 to about 3 moles per moleof Compound (LXIX′).

[1005] Said “base” may for example be an inorganic base, basic salt andthe like. The amount of the base employed is about 1 to about 5 moles,preferably about 1 to about 3 moles per mole of Compound (LXIX′).

[1006] This reaction is conducted advantageously using a solvent whichis inert to the reaction. While such a solvent is not limitedparticularly as long as the reaction is proceeded, it may for example bea solvent such as alcohol, ether, hydrocarbon, amide, halogenatedhydrocarbon, sulfoxide and water as well as a mixture thereof.

[1007] The reaction time is usually about 30 minutes to about 36 hours,preferably about 1 hour to about 24 hours. The reaction temperature isusually about −20 to about 100° C., preferably about 0 to about 80° C.

[1008] Other hydrolysis reaction conditions are those described inJIKKENKAGAKUKOZA 22, 4th edition (Ed. by Japanese Association ofChemistry), pages 151 to 153.

[1009] A reducing agent employed in a subsequent reduction may forexample be metal hydride such as aluminum hydride and diisobutylaluminumhydride, etc., a metal hydrogen complex such as lithium aluminum hydrideand sodium borohydride, etc., a metal such as zinc, aluminum, tin andiron, etc. The amount of a reducing agent employed is about 1 to about10 moles, preferably about 1 to about 5 moles per mole of Compound(LXIX′) when a metal hydride or metal hydrogen complex is employed,while it was about 1 to about 20 equivalents, preferably about 1 toabout 5 equivalents when a metal is employed. In this reaction, a Lewisacid may be employed if desired. Said “Lewis acid” may for example bealuminum chloride, aluminum bromide, titanium (IV) chloride, tin (II)chloride, zinc chloride, boron trichloride, boron tribromide, borontrifluoride and the like. The amount of a Lewis acid employed is about 1to about 10 moles, preferably about 1 to about 5 moles per mole ofCompound (LXIX′).

[1010] This reaction is conducted advantageously using a solvent whichis inert to the reaction. While such a solvent is not limitedparticularly as long as the reaction is proceeded, it may for example bea solvent such as an alcohol, ether, hydrocarbon, amide and organic acidas well as a mixture thereof.

[1011] The reaction time is usually about 1 hour to about 100 hours,preferably about 1 hour to about 50 hours, although it may varydepending on the type and the amount of the reducing agent employed. Thereaction temperature is usually about −20 to about 120° C., preferablyabout 0 to about 80° C.

[1012] Compound (XXVIb′) is produced also by reducing Compound (LXIX′)directly.

[1013] The reducing agent employed in such a reduction may for examplebe a metal hydride such as aluminum hydride and diisobutylaluminumhydride, etc., a metal hydrogen complex such as lithium aluminum hydrideand sodium borohydride, a metal such as zinc, aluminum, tin and iron.The amount of a reducing agent employed is about 1 to about 10 moles,preferably about 1 to about 5 moles per mole of Compound (LXIX′) when ametal hydride or metal hydrogen complex is employed, while it was about1 to about 20 equivalents, preferably about 1 to about 5 equivalentswhen a metal is employed. In this reaction, a Lewis acid may be employedif desired. Said “Lewis acid” may for example be aluminum chloride,aluminum bromide, titanium (IV) chloride, tin (II) chloride, zincchloride, boron trichloride, boron tribromide, boron trifluoride and thelike. The amount of a Lewis acid employed is about 1 to about 10 moles,preferably about 1 to about 5 moles per mole of Compound (LXIX′).

[1014] A hydrogenation reaction may also serve for the reduction, and insuch a case a catalyst such as Pd/C, platinum (IV) oxide, Raney nickeland Raney cobalt, etc. may be employed. The amount of a catalystemployed is about 5 to about 1000% by weight, preferably about 10 toabout 300% by weight, based on Compound (LXIX′). This reaction mayemploy an amine such as ammonia, etc. if desired. The amount of theamine employed is about 1 to about 50 moles, preferably about 1 to about20 moles per mole of Compound (LXIX′). It is also possible that varioushydrogen sources may be employed instead of gaseous hydrogen. Said“hydrogen source” may for example be formic acid, ammonium formate,triethylammonium formate, sodium phosphinate, hydrazine and the like.The amount of such a hydrogen source is about 1 to about 10 moles,preferably about 1 to about 5 moles, per mole of Compound (LXIX′).

[1015] This reaction is conducted advantageously using a solvent whichis inert to the reaction. While such a solvent is not limitedparticularly as long as the reaction is proceeded, it may for example bea solvent such as an alcohol, ether, hydrocarbon, amide and organic acidas well as a mixture thereof.

[1016] The reaction time is usually about 1 hour to about 100 hours,preferably about 1 hour to about 50 hours, although it may varydepending on the type and the amount of the reducing agent employed andthe activity and the amount of the catalyst. The reaction temperature isusually about −20 to about 120° C., preferably about 0 to about 80° C.When a hydrogenation catalyst is employed, the pressure of hydrogen isusually about 1 to about 100 atm.

[1017] Compound (XXVIb′) is produced also from Compound (LXVIII′)similarly to the production of Compound (XXVIb′) from Compound (LXIX′).

[1018] Compound (XXVIIIa′) is produced from Compound (XXVIb′) andCompound (XXVII′) similarly to the production of Compound (XXVIII′) fromCompound (XXVI′) and Compound (XXVII′).

[1019] Compound (I′) is produced from Compound (XXVIIIa′) similarly tothe production of Compound (I′) from Compound (XXVIII′).

[1020] In each of the reactions described above, a starting compoundhaving an amino, carboxy or hydroxy as its substituent may be present asa compound in which a protective group employed ordinarily in a peptidechemistry has been introduced into such a substituent, and an intendedcompound can be obtained by deprotection if necessary after thereaction.

[1021] A protective group for an amino may for example be a formyl oreach optionally substituted C₁₋₆ alkyl-carbonyl (for example, acetyl,propionyl, etc.), benzoyl, C₁₋₆ alkoxy-carbonyl (for example,methoxycarbonyl, ethoxycarbonyl, etc.), phenyloxycarbonyl, C₇₋₁₀aralkyloxy-carbonyl (for example, benzyloxycarbonyl, etc.), trityl,phthaloyl and the like. Its substituent may for example be a halogenatom (for example, fluorine, chlorine, bromine, iodine, etc.), C₁₋₆alkyl-carbonyl (for example, acetyl, propionyl, valeryl, etc.), nitroand the like, and the number of the substituents may be 1 to 3.

[1022] A protective group for a carboxy may for example be eachoptionally substituted C₁₋₆ alkyl (for example, methyl, ethyl, propyl,isopropyl, butyl, tert-butyl, etc.), phenyl, trityl, silyl and the like.Its substituent may for example be a halogen atom (for example,fluorine, chlorine, bromine, iodine, etc.), formyl, C₁₋₆ alkyl-carbonyl(for example, acetyl, propionyl, butylcarbonyl, etc.), nitro, C₁₋₆ alkyl(for example, methyl, ethyl, tert-butyl, etc.) and C₆₋₁₀ aryl (forexample, phenyl, naphthyl, etc.), and the number of the substituents maybe 1 to 3.

[1023] A protective group for a hydroxy may for example be a formyl oreach optionally substituted C₁₋₆ alkyl (for example, methyl, ethyl,propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, C₇₋₁₁ aralkyl (forexample, benzyl, etc.), C₁₋₆ alkyl-carbonyl (for example, acetyl,propionyl, etc.), phenyloxycarbonyl, C₇₋₁₁ aralkyloxy-carbonyl (forexample, benzyloxycarbonyl, etc.), tetrahydropyranyl, tetrahydrofuranyl,silyl and the like. Its substituent may for example be a halogen atom(for example, fluorine, chlorine, bromine, iodine, etc.), C₁₋₆ alkyl(for example, methyl, ethyl, tert-butyl, etc.), C₇₋₁₁ aralkyl (forexample, benzyl, etc.), C₆₋₁₀ aryl (for example, phenyl, naphthyl,etc.), nitro, etc., and the number of the substituents may be 1 to 3.

[1024] A deprotection method may be a method known per se such as atreatment with an acid, base, UV, hydrazine, phenylhydrazine, sodiumN-methyldithiocarbamate, tetrabutylammonium fluoride, Palladium (II)acetate and the like, as well as a reduction.

[1025] In any case, a deprotection, acylation, alkylation,hydrogenation, oxidation, reduction, carbon chain elongation andsubstituent exchange reaction are further employed if necessary alone orin combination with each other to synthesize Compound (A), (I), (I′),(A-1), (I-1) or (I′-1). These reactions may employ the methods describedfor example in SINJIKKENKAGAKUKOZA, Vols.14 and 15, 1977 (MARUZEN) andthe like.

[1026] When an objective product is obtained in a free form by areaction described above, then it may be converted in accordance with anordinary method into a salt, and when it is obtained as a salt then itmay be converted in accordance with an ordinary method into a free formor another salt. Compound (A), (II), (A-1), (I-1) or (I′-1) thusobtained can be isolated and purified from a reaction solution by aknown method such as a partition, concentration, solvent extraction,fraction distillation, crystallization, recrystallization,chromatography and the like.

[1027] When Compound (A), (I), (I′), (A-1), (I-1) or (I′-1) is presentas a configuration isomer, diastereomer, conformer and the like, then itcan be isolated if desired by a separation or purification proceduredescribed above. When Compound (A), (I), (I′), (A-1), (I-1) or (I′-1) ispresent as a racemate, it can be resolved into S form and R form by anordinary optical resolution method.

[1028] When Compound (A), (I), (I′), (A-1), (I-1) or (I′-1) has itsstereoisomers, then individual isomers or a mixture thereof may alsoencompassed in the invention.

[1029] Compound (A), (I), (I′), (A-1), (I-1) or (I′-1) may be a hydrateor anhydrous substance.

[1030] Compound (A), (I), (I′), (A-1), (I-1) or (I′-1) may be labeledwith an isotope (for example, ³H, ¹⁴C, ³⁵S) and the like.

[1031] A compound represented by Formula:

[1032] (wherein each of R^(2a) and R^(3a) is an optionally substitutedaliphatic hydrocarbon group or acyl group,

[1033] R^(4a) is a hydrogen atom, optionally substituted hydrocarbongroup, acyl group or optionally substituted hydroxy group,

[1034] R^(5a) is an optionally substituted hydrocarbon group, acylgroup, optionally substituted heterocyclic group or halogen atom,

[1035] Each of R^(6a), R^(7a), R^(8a) and R^(9a) is a hydrogen atom oroptionally substituted hydrocarbon group,

[1036] X^(a) is a bond, oxygen atom, optionally oxidized sulfur atom oroptionally substituted nitrogen atom), or by Formula:

[1037] (wherein each of R^(2a) and R^(3a) is an optionally substitutedaliphatic hydrocarbon group or acyl group,

[1038] R^(4a) is a hydrogen atom, optionally substituted hydrocarbongroup, acyl group or optionally substituted hydroxy group,

[1039] R^(5a) is an optionally substituted hydrocarbon group, acylgroup, optionally substituted heterocyclic group or halogen atom,

[1040] Each of R^(6a), R^(7a), R^(8a) and R^(9a) is a hydrogen atom oroptionally substituted hydrocarbon group,

[1041] X^(a) is a bond, oxygen atom, optionally oxidized sulfur atom oroptionally substituted nitrogen atom,

[1042] Z is an optionally substituted hydroxy group or halogen atom, ora salt thereof, is a novel compound.

[1043] An “aliphatic hydrocarbon group” of an “optionally substitutedaliphatic hydrocarbon group” represented by R^(2a) and R^(3a) may forexample be a linear hydrocarbon or alicycllc hydrocarbon group such asan alkyl group, alkenyl group, alkynyl group, cycloalkyl group and thelike, with a linear (straight or branched) or alicyclic hydrocarbongroup having 1 to 16 carbon atoms being preferred. Specifically, thoselisted below are employed.

[1044] (1) Linear hydrocarbon groups:

[1045] alkyl groups [preferably, a lower alkyl group (for example, aC₁₋₆ alkyl group such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like)],

[1046] (2) Alicyclic hydrocarbon groups:

[1047] cycloalkyl groups [preferably, a lower cycloalkyl group (forexample, a C₃₋₆ cycloalkyl group such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and the like) and this lower cycloalkyl groupmay be fused with benzene ring.],

[1048] and a substituent on such a “aliphatic hydrocarbon group” may forexample be a group selected from the group (hereinafter referred to asSubstituent Group B) consisting of (1) a halogen atom, (2) a C₁₋₃alkylenedioxy group, (3) a nitro group, (4) an optionally halogenatedC₁₋₆ alkyl group, (5) a C₃₋₆ cycloalkyl group, (6) a C₆₋₁₄ aryl group,(7) an optionally halogenated C₁₋₆ alkoxy group, (8) an optionallyhalogenated C₁₋₆ alkylthio group, (9) a hydroxy group, (10) an aminogroup, (11) a mono-C₁₋₆ alkylamino group, (12) a mono-C₆₋₁₄ arylaminogroup, (13) a di-C₁₋₆ alkylamino group, (14) a di-C₆₋₁₄ arylamino group,(15) an acyl group selected from formyl, carboxy, carbamoyl, C₁₋₆alkyl-carbonyl, C₃₋₆ cycloalkyl-carbonyl, C₁₋₆ alkoxy-carbonyl, C₆₋₁₄aryl-carbonyl, C₇₋₁₆ aralkyl-carbonyl, C₆₋₁₄ aryloxy-carbonyl, C₇₋₁₆aralkyloxy-carbonyl, (5- or 6-membered heterocycle having, in additionto carbon atoms, 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms)-carbonyl, mono-C₁₋₆ alkyl-carbamoyl, di-C₁₋₆alkyl-carbamoyl, C₆₋₁₄ aryl-carbamoyl, (5- or 6-membered heterocyclehaving, in addition to carbon atoms, 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms)-carbamoyl, C₁₋₆ alkyl-thiocarbonyl,C₃₋₆ cycloalkyl-thiocarbonyl, C₁₋₆ alkoxy-thiocarbonyl, C₆₋₁₄aryl-thiocarbonyl, C₇₋₁₆ aralkyl-thiocarbonyl, C₆₋₁₄aryloxy-thiocarbonyl, C₇₋₁₆ aralkyloxy-thiocarbonyl, (5- or6-membered-heterocycle having, in addition to carbon atoms, 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygenatoms)-thiocarbonyl, thiocarbamoyl, mono-C₁₋₆ alkyl-thiocarbamoyl,di-C₁₋₆ alkyl-thiocarbamoyl, C₆₋₁₄ aryl-thiocarbamoyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbamoyl,mono-C₁₋₆ alkylsulfamoyl, di-C₁₋₆ alkylsulfamoyl, C₆₋₁₄ arylsulfamoyl,C₁₋₆ alkylsulfonyl, C₆₋₁₄ arylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₄arylsulfinyl, sulfino, sulfo, C₁₋₆ alkoxysulfinyl, C₆₋₁₄aryloxysulfinyl, C₁₋₆ alkoxysulfonyl and C₆₋₁₄ aryloxysulfonyl, (16) anacylamino group selected from formylamino, C₁₋₆ alkyl-carboxamido, C₆₋₁₄aryl-carboxamido, C₁₋₆ alkoxy-carboxamido, C₁₋₆ alkylsulfonylamino andC₆₋₁₄ arylsulfonylamino, (17) an acyloxy group selected from C₁₋₆aLkyl-carbonyloxy, C₆₋₁₄ aryl-carbonyloxy, C₁₋₆ alkoxy-carbonyloxy,mono-C₁₋₆ alkyl-carbamoyloxy, di-C₁₋₆ alkyl-carbamoyloxy, C₆₋₁₄aryl-carbamoyloxy and nicotinoyloxy, (18) a 4- to 14-memberedheterocyclic group having, in addition to carbon atoms, 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygen atoms, (19) aphosphono group, (20) a C₆₋₁₄ aryloxy group, (21) a di-C₁₋₆alkoxy-phosphoryl group, (22) a C₆₋₁₄ arylthio group, (23) a hydrazinogroup, (24) an imino group, (25) an oxo group, (26) an ureldo group,(27) a C₁₋₆ alkyl-ureido group, (28) a di-C₁₋₆-alkyl-ureido group, (29)an oxide group and (30) a group formed by binding 2 or 3 groups selectedfrom (1) to (29) listed above. Those exemplified typically as thesesubstituents are those exemplified with regard to Substituent Group Adescribed above.

[1049] An “acyl group” represented by R^(2a) and R^(3a) is one similarto an “acyl group” represented by R² and R³.

[1050] Any of “optionally substituted hydrocarbon group”, “acyl group”and “optionally substituted hydroxy group” represented by R^(4a) is onesimilar to any of “optionally substituted hydrocarbon group”, “acylgroup” and “optionally substituted hydroxy group” represented by R⁴.

[1051] Any of “optionally substituted hydrocarbon group”, “acyl group”,“optionally substituted heterocyclic group” and “halogen atom”represented by R^(5a) is one similar to any of “optionally substitutedhydrocarbon group”, “acyl group”, “optionally substituted heterocyclicgroup” and “halogen atom” represented by R⁵.

[1052] An “optionally substituted hydrocarbon group” represented byR^(6a), R^(7a), R^(8a) and R^(9a) is one similar to an “optionallysubstituted hydrocarbon group” represented by R⁶ ₁ R⁷, R⁸ and R⁹.

[1053] Any of “optionally oxidized sulfur atom” and “optionallysubstituted nitrogen atom” represented by X^(a) is one similar to an“optionally-oxidized sulfur atom” or “optionally substituted nitrogenatom” represented by X.

[1054] An “optionally substituted hydroxy group” represented by Z mayfor example be a group represented by Formula: —OZ^(a) wherein Z^(a) isa hydrogen atom, optionally substituted hydrocarbon group or acyl group.

[1055] Any of “optionally substituted hydrocarbon group” and “acylgroup” represented by Z^(a) is one similar to any of “optionallysubstituted hydrocarbon group” and “acyl group” represented by R².

[1056] A halogen atom represented by Z is a fluorine atom, chlorineatom, bromine atom and iodine atom.

[1057] Compounds (B) and (C) are preferably those listed below.

[1058] (1) Compounds (B) and (C) wherein each of R^(2a) and R^(3a) is(1) a C₁₋₆ alkyl group which may be substituted by <1> a halogen atom,<2> a hydroxy group which may be substituted by a substituent selectedfrom a C₁₋₆ alkyl, C₁₋₆ alkyl-carbonyl, C₁₋₆ alkylsulfonyl and C₇₋₁₆aralkyl, <3> an amino group which may be substituted by 1 or 2 C₁₋₆alkyl, C₁₋₆ alkyl-carbonyl and C₆₋₁₄ aryl-carbonyl, <4> a 4- to10-membered heterocyclic group containing 1 to 3 heteroatom(s) selectedfrom nitrogen, oxygen and sulfur atoms in addition to carbon atoms, <5>a thio group which may be substituted by C₁₋₆ alkyl, <6> a C₁₋₆alkyl-sulfinyl group or <7> a C₁₋₆ alkyl-sulfonyl group or (2) a C₁₋₆alkoxy-carbonyl group,

[1059] R^(4a) is (i) a hydrogen atom, (ii) a C₁₋₆ alkyl group [this C₁₋₆alkyl group may have a substituent selected from (1) a halogen atom, (2)a C₁₋₆ alkoxy group, (3) a hydroxy group, (4) an amino group, (5) amono-C₁₋₆ alkylamino group, (6) a di-C₁₋₆ alkylamino group, (7) a 4- to10-membered heterocyclic group containing 1 to 3 heteroatom(s) selectedfrom nitrogen, sulfur and oxygen atoms in addition to carbon atoms whichmay have an oxo, (8) a C₆₋₁₄ arylthio, (9) an ureido, (10) a carboxy,(11) a carbamoyl, (12) a C₁₋₆ alkoxy-carbonyl, (13) a mono-C₁₋₆alkyl-carbamoyl, (14) a formylamino and (15) a C₁₋₆ alkyl-carboxamido]or (iii) a formyl group;

[1060] X^(a) is a bond, oxygen atom, optionally oxidized sulfur atom,—NH— or —N(methyl)-,

[1061] R^(5a) is,

[1062] when X^(a) is a bond, then (i) a C₁₋₆ alkyl group or (ii) ahalogen atom,

[1063] when X^(a) is an oxygen atom, then (i) a C₁₋₆ alkyl group [thisC₁₋₆ alkyl group may have a substituent selected from (1) a halogenatom, (2) a hydroxy group, (3) an amino group, (4) a carboxy, (5) acarbamoyl, (6) a C₁₋₆ alkoxy-carbonyl, (7) a mono-C₁₋₆ alkyl-carbamoyl,(8) a di-C₁₋₆ alkyl-carbamoyl, (9) a 4- to 10-membered heterocyclicgroup containing 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms in addition to carbon atoms], (ii) a C₃₋₆ cycloalkyl group,(iii) a C₇₋₁₆ aralkyl group, (iv) a C₁₋₆ alkyl-carbonyl group, (v) aC₆₋₁₄ aryl-carbonyl group, (vi) a C₁₋₆ alkoxy-carbonyl group, (vii) amono- or di-C₁₋₆ alkyl-thiocarbamoyl group, (viii) an optionallyhalogenated C₁₋₆ alkyl-sulfonyl group or (ix) a 4- to 10-memberedheterocyclic group containing 1 to 4 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms in addition to carbon atoms [thisheterocyclic group may have a C₆₋₁₄ aryl],

[1064] when X^(a) is an optionally oxidized sulfur, then (i) a C₁₋₆alkyl group or (ii) a mono- or di-C₁₋₆ alkyl-carbamoyl group,

[1065] when X^(a) is —NH— or —N(methyl)-, then (i) a C₁₋₆ alkyl group[this C₁₋₆ alkyl group may have a C₁₋₆ alkoxy-carbonyl], (ii) formyl,(iii) a C₁₋₆ alkyl-carbonyl group, (iv) a C₁₋₆ alkoxy-carbonyl group,(v) a carbamoyl group, (vi) a mono- or di-C₁₋₆ alkyl-carbamoyl group or(vii) a C₁₋₆ alkyl-sulfonyl group,

[1066] each of R^(6a), R^(7a), R^(8a) and R^(9a) is a hydrogen atom orC₁₋₆ alkyl group,

[1067] Z is (i) a hydroxy group which may be substituted by a C₁₋₆alkyl-carbonyl or (ii) a halogen atom.

[1068] (2) Compounds (B) produced in Reference Examples 5, 6, 26, 27,30, 57, 60, 63, 95 and 137.

[1069] (3) Compounds (C) produced in Reference Examples 7, 8 and 115.

[1070] A prodrug for an inventive Compound (I), (I′), (I-1) or (I′-1) isa compound which is converted into Compound (I), (I′), (I-1) or (I′-1)under a physiological condition as a result of a reaction with an enzymeor gastric acid, thus a compound undergoing an enzymatic oxidation,reduction or hydrolysis to form Compound (I), (I′), (I-1) or (I′-1) anda compound hydrolyzed by gastric acid to form Compound (I), (I′), (I-1)or (I′-1). A prodrug for Compound (I), (I′), (I-1) or (I′-1) may forexample be a compound obtained by subjecting an amino group in Compound(I), (I′), (I-1) or (I′-1) to an acylation, alkylation orphosphorylation (e.g., a compound obtained by subjecting an amino groupin Compound (I), (I′), (I-1) or (I′-1) to an eicosanoylation,alanylation, pentylaminocarbonylation,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylationand tert-butylation, etc.); a compound obtained by subjecting a hydroxygroup in Compound (I), (I′), (I-1) or (I′-1) to an acylation,alkylation, phosphorylation or boration (e.g., a compound obtained bysubjecting an hydroxy in Compound (I), (I′), (I-1) or (I′-1) to anacetylation, palmitoylation, propanoylation, pivaloylation,succinylation, fumarylation, alanylation,dimethylaminomethylcarbonylation, etc.); a compound obtained bysubjecting a carboxy group in Compound (I), (I′), (I-1) or (I′-1) to anesterification or amidation (e.g., a compound obtained by subjecting acarboxy group in Compound (I), (I′), (I-1) or (I′-1) to anethylesterification, phenylesterification, carboxymethylesterification,dimethylaminomethylesterification, pivaloyloxymethylesterification,ethoxycarbonyloxyethylesterification, phthalidylesterification,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methylesterification,cyclohexyloxycarbonylethylesterification and methylamidation, etc.) andthe like. Any of these compounds can be produced from Compound (I),(I′), (I-1) or (I′-1) by a method known per se.

[1071] A prodrug for Compound (I), (I′), (I-1) or (I′-1) may also be onewhich is converted into Compound (I), (I′), (I-1) or (I′-1) under aphysiological condition, such as those described in “IYAKUHIN noKAIHATSU (Development of Pharmaceuticals)”, Vol.7, Design of Molecules,p.163-198, Published by HIROKAWA SHOTEN (1990).

[1072] As a salt of Compound (A), (I), (I′), (A-1), (I-1), (I′-1), (B)or (C) may for example be a physiologically acceptable salt. Forexample, a salt with an inorganic base, ammonium, organic base,inorganic acid, organic acid, basic or acidic amino acid may beemployed. A salt with an inorganic base may for example be an alkalinemetal salt such as sodium and potassium salts, etc., an alkaline earthmetal salt such as calcium and magnesium salts, etc., aluminum and thelike. A salt with an organic base may for example be a salt with.trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine,ethanolamine, diethanolamine, triethanolamine, cyclohexylamine,dicyclohexylamine or N,N′-dibenzylethylenediamine, etc. A salt with aninorganic acid may for example be a salt with hydrochloric acid,hydrobromic acid, nitric acid, sulfuric acid or phosphoric acid, etc. Asalt with an organic salt may for example be a salt with formic acid,acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalicacid, tartaric acid, maleic acid, citric acid, succinic acid, malicacid, methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonicacid, etc. A salt with a basic amino acid may for example be a salt witharginine, lysine or ornithine, etc., and a salt with acidic amino acidmay for example be a salt with aspartic acid or glutamic acid, etc.

[1073] Among those listed above, a pharmacologically acceptable salt ispreferred, including, a salt with an inorganic acid such as hydrochloricacid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid,etc., a salt with an organic acid such as acetic acid, phthalic acid,fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid,methanesulfonic acid and p-toluenesulfonic acid, etc. when Compound (I)or (I′) has a basic functional group, as well as an alkaline metal saltsuch as sodium salt and potassium salt, etc., an alkaline earth metalsalt such as calcium salt and magnesium salt, etc., and an ammonium saltwhen Compound (I) or (I′) has a acidic functional group.

[1074] Since Compound (A), (I), (I′), (A-1), (I-1), (I′-1) according tothe invention or a salt thereof (including a prodrug for Compound (I),(I-1), (I′), (I′-1)) (hereinafter abbreviated as an inventive compound)has an excellent phosphodiesterase (PDE) IV-inhibiting effect and a lowtoxicity and also is safe, it can be employed as a prophylactic ortherapeutic agent in mammals (for example, human, mouse, dog, rat,cattle, etc.) against inflammatory diseases, for example, bronchialasthma, chronic obstructive pulmonary disease (COPD), rheumatoidarthritis, autoimmune disease, diabetes, graft versus host disease,multiple sclerosis, sepsis, psoriasis, osteoporosis, depression, centraldysfunction after cerebrovascular occlusion, cerebrovascular dementia,Alzheimer dementia, obesity, cardiac insufficiency, atopic dermatitisand the like, as well as a phosphodiesterase (PDE) IV inhibitor. Theadministration route may be oral or parenteral.

[1075] A specific dosage form may for example be a tablet (includingsugar-coated and film-coated tablets), pill, capsule (includingmicrocapsule), granule, fine powder, powder, syrup, emulsion, injectionformulation, inhalation formulation, ointment, eye drop, aerosol,ophthalmic ointment, hard ointment, suppository, troche, poulitic,liniment and the like. Any of these formulations can be prepared inaccordance with an ordinary method (for example a method described inJapanese Pharmacopoeia).

[1076] The amount of an inventive compound in a formulation according tothe invention may vary depending on the dosage form, and it is usually0.01 to 100% by weight based on the entire formulation, preferably 0.1to 50% by weight, more preferably 0.5 to 20% by weight.

[1077] Specifically, a tablet is produced by mixing a medicament as itis with an excipient, binder, disintegrant or other suitable additivesto form a homogenous mass, granulating by a suitable method, combiningwith a lubricant and the like, and then compressing into a tablet, or bymixing a medicament as it is with an excipient, binder, disintegrant orother suitable additives to form a homogenous mass and then compressingdirectly into a tablet, or by preparing a granule first and thencompressing into a tablet directly or after mixing with suitableadditives to form a homogenous mass. The formulation can further containcolorants, seasonings and the like, if necessary. The formulation canfurther be film-coated by a suitable coating.

[1078] In a method for producing an injection formulation, a certainamount of a medicament is dissolved, suspended or emulsified in a waterfor injection, physiological saline and Ringer's solution when themedicament is water-soluble, or usually in a vegetable oil when themedicament is water-insoluble, whereby obtaining a certain quantity, ora certain amount of the medicament is enclosed in a vial for aninjection formulation.

[1079] An oral formulation carrier is a material employed customarily inthe pharmaceutical field, such as starch, mannitol, crystallinecellulose, sodium carboxymethylcellulose and the like. A vehicle forinjection may for example be distilled water, physiological saline,glucose solution, infusion solution and the like. Other additivesgenerally employed in a formulation may also be added properly.

[1080] While the dose of such a formulation may vary depending on theage, body weight, condition, administration route, administrationfrequency and the like, a daily dose in an adult having asthma isusually 0.01 to 100 mg/kg as an active ingredient (inventive compound),preferably 0.01 to 50 mg/kg, more preferably 0.05 to 10 mg/kg, which isgiven orally once or in two portions a day.

[1081] While the compound of the invention can exhibit an excellentphosphodiesterase (PDE) IV-inhibiting activity even when being givenalone, it can be used also in combination (multimedicament combination)with pharmaceutical components other than inventive compounds(hereinafter referred to as concomitant medicaments).

[1082] Such a concomitant medicament may for example be an antiasthmaagent (for example, fluticasone propionate, beclomethasone propionate,theophylline, procaterol, ketotifen, azelastine, seratrodast, etc.),anti-allergic agent (for example, fexofenadine, epinastine, ebastine,etc.), anti-cholinergic agent (for example ipratropium bromide,flutropium bromide, oxitropium bromide, etc.), anti-inflammatory agent(for example, diclofenac sodium, ibuprofen, indomethacin, loxoprofensodium, etc.), antibacterial agent (for example, cefixime, cefdinir,ofloxacin, tosufloxacin tosilate, levofloxacin, etc.), antifungal agent(for example, fluconazole, itraconazole, etc.), diabetes-treating agent(for example, pioglitazone, nateglinide, voglibose, acarbose, etc.),etc.

[1083] When using an inventive compound in combination with aconcomitant medicament, the timings of the administration of theinventive compound and the concomitant medicament are not particularlylimited, and the inventive compound and the concomitant medicament canbe given to a subject simultaneously or at a certain time interval. Thedose of the concomitant medicament may be in accordance with a doseemployed clinically, and selected appropriately depending on the target,route, disease, combination and the like.

[1084] The administration mode of an inventive compound and aconcomitant medicament are not particularly limited, provided that theinventive compound and the concomitant medicament are combined uponadministration. Such an administration mode may for example be (1) anadministration of a single formulation obtained by formulating aninventive compound and a concomitant medicament simultaneously, (2) asimultaneous administration via an identical route of two formulationsobtained by formulating an inventive compound and a concomitantmedicament separately, (3) a sequential and intermittent administrationvia an identical route of two formulations obtained by formulating aninventive compound and a concomitant medicament separately, (4) asimultaneous administration via different routes of two formulationsobtained by formulating an inventive compound and a concomitantmedicament separately, (5) a sequential and intermittent administrationvia different routes of two formulations obtained by formulating aninventive compound and a concomitant medicament separately (for example,inventive compound followed by concomitant medicament, or inverse order)and the like. These administration modes are hereinafter referred to asan inventive concomitant preparation.

[1085] An inventive concomitant preparation has a low toxicity, and thusan inventive compound and/or a concomitant medicament described aboveare mixed with a pharmacologically acceptable carrier in accordance witha method known per se to form a. pharmaceutical composition, forexample, a tablet (including sugar-coated and film-coated tablets),powder, granule, capsule (including softcapsule), solution, injectionformulation, suppository, sustained release formulation and the like,which can safely be given orally or parenteraly.(e.g., topically,rectally, intravenously). An injection formulation may be givenintravenously, intramuscularly, subcutaneously, into an organ,intranasally, intradermally, via eye drop, intracerebrally, rectally,vaginally and intraperitoneally, or into a tumor, or proximal to thetumor, or directly into a lesion.

[1086] A pharmacologically acceptable carrier which may be employed forproducing an inventive concomitant preparation may for example be onesimilar to those employed in an inventive pharmaceutical compositiondescribed above.

[1087] The ratio between an inventive compound and a concomitantmedicament in an inventive concomitant preparation may be selectedappropriately on the basis of the target, route and disease, etc.

[1088] For example, the amount of an inventive compound contained in aninventive concomitant preparation is usually about 0.01 to 100% byweight based on the entire formulation, preferably about 0.1 to about50% by weight, more preferably about 0.5 to about 20% by weight,although it may vary depending on the dosage form.

[1089] The amount of an concomitant medicament contained in an inventiveconcomitant preparation is usually about 0.01 to 100% by weight based onthe entire formulation, preferably about 0.1 to about 50% by weight,more preferably about 0.5 to about 20% by weight, although it may varydepending on the dosage form.

[1090] The amount of an additive such as a carrier contained in aninventive concomitant preparation is usually about 1 to about 99.99% byweight based on the entire formulation, preferably about 10 to about 90%by weight, although it may vary depending on the dosage form.

[1091] Similar amounts may be employed also when an inventive compoundand a concomitant medicament are formulated separately.

[1092] Such a formulation can be produced by a method known per se whichis employed usually in a pharmaceutical process.

[1093] For example, an inventive compound and a concomitant medicamentcan be formulated with a dispersant (e.g., Tween 80 (ATLAS POWDER, USA),HCO60 (NIKKO CHEMICALS), polyethylene. glycol, carboxymethyl cellulose,sodium alginate hydroxypropylmethyl cellulose, dextrin, etc.), astabilizer (e.g., ascorbic acid, sodium pyrosulfite, etc.), a surfactant(e.g., polysorbate 80, macrogol, etc.), a solubilizing agent (e.g.,glycerin, ethanol, etc.), buffer agent (e.g., phosphoric acid and itsalkali metal salts, citric acid and its alkali metal salt, etc.), anosmotic agent (e.g., sodium chloride, potassium chloride, mannitol,sorbitol, glucose, etc.), a pH modifier (e.g., hydrochloric acid, sodiumhydroxide, etc.), a preservative (e.g., ethyl p-hydroxybenzoate, benzoicacid, methylparabene, propylparabene, benzyl alcohol, etc.), asolubilizer (e.g., concentrated glycerin, meglumine, etc.), asolubilizing aid (e.g., propylene glycol, sugar, etc.), a painkiller(e.g., glucose, benzyl alcohol, etc.), etc. into an aqueous formulationfor injection, or dissolved, suspended or emulsified in a vegetable oilsuch as olive oil, sesame oil, cottonseed oil and corn oil, etc. and ina solubilizing aid such as propylene glycol, etc. to form an oilyformulation, whereby producing an injection formulation.

[1094] In order to obtain an oral dosage form, a method known per se isemployed to compress an inventive compound or a concomitant medicamentfor example with an excipient (e.g., lactose, sugar, starch, etc.), adisintegrant (e.g., starch, calcium carbonate, etc.), a binder (e.g.,starch, gum arabic, carboxymethyl cellulose, polyvinyl pyrrolidone,hydroxypropyl cellulose, etc.) or a glidant (e.g., talc, magnesiumstearate, polyethylene glycol 6000, etc.) into a desired shape, which isthen subjected to a taste masking, covered with an enteric coating orimparted with a sustained release performance if necessary by means of acoating method known per se, whereby obtaining an oral dosage form. Sucha coating may for example be hydroxypropylmethyl cellulose, ethylcellulose, hydroxymethyl cellulose, hydroxypropyl cellulose,polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose acetatephthalate, hydroxypropylmethyl cellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (Rohm, German, methacrylic/acrylicacid copolymer) and a colorant (e.g., iron oxide red, titanium dioxide,etc.). An oral dosage form may be an instantaneous release formulationor a sustained release formulation.

[1095] In order to obtain for example a suppository, a method known perse is employed to convert an inventive compound or concomitantmedicament into an oily or aqueous solid, semi-solid or liquidsuppository. The oily base employed in a composition described above mayfor example be a higher fatty acid glyceride [e.g., cocoa butter,UITEPSOL (DYNAMITE NOVEL, Germany), etc.], a medium fatty acid [e.g.,MIGRIOL (DYNAMITE NOVEL, Germany), etc.], or a vegetable oil (e.g.,sesame oil, soybean oil, cottonseed oil, etc.), etc. The aqueous basemay for example be polyethylene glycol and propylene glycol, and theaqueous gel base may for example be natural gums, cellulose derivatives,vinyl polymers and acrylic acid polymers, etc.

[1096] A sustained release formulation described above may for examplebe a sustained-release microcapsule, etc.

[1097] While a sustained-release microcapsule can be obtained by amethod known per se, a sustained release formulation shown in Section[2] described below is formed and administered in a preferred case.

[1098] The inventive compound is preferably formulated as an oral dosageform such as a solid formulation (e.g., powder, granule, tablet,capsule, etc.), or as a rectal formulation such as a suppository, etc.The oral dosage form is particularly preferred.

[1099] A concomitant medicament can be formulated into a dosage formdescribed above based on the type of the medicament.

[1100] The followings are the descriptions with regard to [1] theinjection formulation of the inventive compound and the concomitantmedicament and the method for producing the same, [2] thesustained-release or immediate release formulation of the medicament ofthe inventive compound and the concomitant medicament and the method forproducing the same and [3] the sublingual, buccal or instant oraldisintegration formulations employing of the inventive compound and theconcomitant medicament and the method for producing the same.

[1101] [1] Injection Formulation and Method for Producing the Same

[1102] The solution obtained by dissolving the inventive compound andthe concomitant medicament in water is employed preferably. Suchinjection formulation may contain a benzoate and/or a salicylate.

[1103] Said injection formulation is obtained by dissolving theinventive compound and the concomitant medicament in water together witha benzoate and/or a salicylate in water as desired.

[1104] The benzoate and/or a salicylate described above may be an alkalimetal salt such as sodium and potassium salts, etc., an alkaline earthmetal salt such as calcium and magnesium salts, etc., an ammonium salt,a meglumine salt as well as a salt of an organic acid such astrometamol, etc.

[1105] The concentration of an inventive compound or a concomitantmedicament in an injection formulation is about 0.5 to about 50 w/v %,preferably about 3 to about 20 w/v %. The concentration of a benzoateand/or a salicylate is about 0.5 to about 50 w/v %, preferably about 3to about 20 w/v %.

[1106] The formulation may contain additives employed customarily in ainjection formulation, such as a stabilizer (ascorbic acid, sodiumpyrosulfite and the like), a surfactant (polysorbate 80, macrogol andthe like), a solubillzing agent (glycerin, ethanol and the like), abuffer agent (phosphoric acid and its alkali metal salt, citric acid andits alkali metal salt and the like), an osmotic agent (sodium chloride,potassium chloride and the like), a dispersing agent(hydroxypropylmethyl cellulose, dextrin), a pH modifier (hydrochloricacid, sodium hydroxide and the like), a preservative (ethylp-hydroxybenzoate, benzoic acid and the like), a solubilizer(concentrated glycerin, meglumine and the like), a solubilizing aid(propylene glycol, sugar and the like), a painkiller (glucose, benzylalcohol and the like) properly. Any of these additives are added in anamount employed customarily in a formulation for injection.

[1107] The pH of the injection formulation is adjusted at 2 to 12,preferably 2.5 to 8.0 with a pH modifier.

[1108] An injection formulation is obtained by dissolving an inventivecompound and a concomitant medicament if desired together with abenzoate and/or sallcylate in water if desired together with theadditives listed above. These components may be dissolved in any orderas appropriate similarly to a customary preparation of a formulation forinjection.

[1109] An injection formulation is preferably warmed, and given as aformulation for injection after sterilizing by filtration or autoclavesimilarly to a customary formulation for injection.

[1110] An injection formulation is preferably autoclaved at 100 to 121°C. for 5 to 30 minutes.

[1111] A formulation may be present as a solution imparted with anantibacterial activity for the purpose of using several times in divideddoses.

[1112] [2] Sustained-release or Immediate Release Formulation and Methodfor Producing the Same

[1113] A sustained release formulation obtained by coating a corecontaining an inventive compound or a concomitant medicament with awater-insoluble material or a swelling polymer as desired is employedpreferably. For example, a sustained-release oral formulation of asingle daily dose is preferred.

[1114] A water-insoluble material employed as a coating may for examplebe cellulose ether such as ethyl cellulose and butyl cellulose, etc.,cellulose ester such as cellulose acetate and cellulose propionate,etc., polyvinyl ester such as polyvinyl acetate and polyvinyl butyrate,etc., acrylic acid-based polymer such as acrylic acid/methacrylic acidcopolymer, methyl methacrylate copolymer, ethoxyethylmethacrylate/cinnamoethyl methacrylate/aminoalkyl methacrylatecopolymer, polyacrylic acid, polymethacrylic acid, metacrylic acidalkylamide copolymer, poly(methyl methacrylate), polymethacrylate,polymethacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylicanhydride), glycidyl methacrylate copolymer, especially, a series ofEudragit such as Eudragit RS-100, RL-100, RS-30D, RL-30D, RL-PO, RS-PO(ethyl acrylate/methyl methacrylate/chlorotrimethyl methacrylate/ethylammonium copolymer) and Eudragit NE-30D (methyl methacrylate/ethylacrylate copolymer), hydrogenated oils such as a hydrogenated castor oil(e.g., Lubri wax (Freund Industrial Co.,Ltd.), waxes such as carnaubawax, a fatty acid glycerin ester and paraffin and a polyglycerin fattyacid ester, etc.

[1115] As a swelling polymer, a polymer having an acidic cleavable groupand exhibiting a pH-dependent swelling is preferred, and an acidiccleavable group-bearing polymer which undergoes a less swelling at anacidic pH such as in stomach but is swollen extensively at a neutral pHsuch as in small and large intestines is preferred.

[1116] Such polymer having an acidic cleavable group and exhibiting apH-dependent swelling may for example be a crosslinked polyacrylic acidpolymer such as Carbomers 934P, 940, 941, 974P, 980, 1342 and the like,Polycarbophil and Calcium Polycarbophil (BF GOODRICH), HIGHVIS Wakos103, 104, 105 and 304 (Wako Pure Chemical).

[1117] A coating employed in a sustained release formulation may furthercontain a hydrophilic material.

[1118] Such hydrophilic material may for example be a polysaccharidewhich may have a sulfate group such as pullulan, dextrin and alkalimetal alginates, a polysaccharide having a hydroxyalkyl group or acarboxyalkyl group such as hydroxypropyl cellulose, hydroxypropylmethylcellulose and sodium carboxymethyl cellulose as well as methylcellulose, polyvinyl pyrrolidone, polyvinyl alcohol and polyethyleneglycol, etc.

[1119] The water-insoluble material content in a coating of a sustainedrelease formulation is about 30 to about 90% (w/w), preferably about 35to about 80% (w/w), more preferably about 40 to about 75% (w/w), and theswelling polymer content is about 3 to about 30% (w/w), preferably about3 to about 15% (w/w). A coating may further contain a hydrophilicmaterial, the content of which in the coating is about 50% (w/w) orless, preferably about 5 to about 40% (w/w), more preferably about 5 toabout 35% (w/w). Percent (w/w) referred here means a % by weight basedon the coating composition which is the rest of the coating solutionafter deleting any solvent (e.g., water and a lower alcohol such asmethanol and ethanol, etc.).

[1120] A sustained release formulation is produced, as exemplifiedbelow, by preparing a core containing a medicament followed by coating aresultant core with a coating solution obtained by melting awater-insoluble material or a swelling polymer or by dissolving ordispersing such material in a solvent.

[1121] I. Drug-containing Core Preparation

[1122] While a coated medicament-containing core (hereinafter sometimesreferred to simply as a core) may be in any non-limiting shape, it isformed preferably as a particle such as a granule or a fine particle.

[1123] When a core is a granule or a fine particle, it has a meanparticle size preferable of about 150 to 2,000 μm, more preferably about500 to 1,400 μm.

[1124] The core can be prepared by a standard method. For example, amedicament is combined with suitable excipient, binder, disintegrant,glidant, stabilizer and the like, and then subjected to a wet extrusiongranulation or a fluidized bed granulation.

[1125] The medicament content in a core is about 0.5 to about 95% (w/w),preferably about 5.0 to about 80% (w/w), more preferably about 30 toabout 70% (w/w).

[1126] The excipient contained in a core may for example be a saccharidesuch as sucrose, lactose, mannitol and glucose, etc., starch,crystalline cellulose, calcium phosphate and corn starch. Among these,crystalline cellulose and corn starch are preferred.

[1127] A binder may for example be polyvinyl alcohol, hydroxypropylcellulose, polyethylene glycol, polyvinyl pyrrolidone, Pluronic F68, gumarabic, gelatin and starch, etc. A disintegrant may for example becalcium carboxymethyl cellulose (ECG505), sodium croscarmellose(Ac-Di-Sol), crosslinked polyvinyl pyrrolidone (crospovldone) and alow-substituted hydroxypropyl cellulose (L-HPS), etc. Among these,hydroxypropyl cellulose, polyvinyl pyrrolidone and a low-substitutedhydroxypropyl cellulose are preferred. A glidanxt and an anticoagulantmay for example be talc, magnesium stearate, etc., and a lubricant mayfor example be polyethylene glycol, etc. A stabilizer may for example bean acid such as tartaric acid, citric acid, succinic acid, fumaric acidand maleic acid, etc.

[1128] In addition to the methods described above, other methods can beemployed to form a core, such as an agitating granulation method whereinan inert carrier particle as a seed for the core is sprayed with abinder dissolved in a suitable solvent such as water and a lower alcohol(e.g., methanol and ethanol) with being supplemented portionwise with amedicament or a mixture thereof with an excipient and a glidant as wellas a pan coating method, a fluidized bed coating method and a meltinggranulation method. An inert carrier particle may for example be oneprepared from sugar, lactose, starch, crystalline cellulose and waxes,and has a mean particle size preferably of about 100 μm to about 1,500μm.

[1129] In order to separate a medicament contained in a core from acoating, the surface of the core may be covered with a protectivematerial. Such protective material may for example be a hydrophilicmaterial described above and a water-insoluble material. A preferredprotective material is polyethylene glycol or a polysaccharide having ahydroxyalkyl group or a carboxyalkyl group, more preferably,hydroxypropylmethyl cellulose and hydroxypropyl cellulose. Theprotective material may contain, as a stabilizer, an acid such astartaric acid, citric acid, succinic acid, fumaric acid and maleic acid,as well as a glidant such as talc, etc. A protective material, whenemployed, is coated at a rate of about 1 to about 15% (w/w), preferablyabout 1 to about 10% (w/w), more preferably about 2 to about 8% (w/w)based on a core.

[1130] A protective material can be coated by a standard coating method,and typically a core is sprayed with the protective material by afluidized bed coating method and a pan coating method.

[1131] II. Coating of Core with Coating Agent

[1132] A core obtained as described above in Section I is coated with acoating solution containing a water-insoluble material, a pH-dependentswelling polymer and a hydrophilic material being melted therein byheating or being dissolved or dispersed in a solvent to obtain asustained release formulation.

[1133] A method for coating a core with a coating solution may forexample be a spray coating.

[1134] The ratio between a water-insoluble material, a swelling polymerand a hydrophilic material in a coating solution may be selectedappropriately in such a manner that respective contents in the coatingbecome those specified above.

[1135] The coating rate is about 1 to about 90% (w/w) based on the core(excluding the protective material coating), preferably about 5 to about50% (w/w), more preferably about 5 to about 35% (w/w).

[1136] The solvent for a coating solution is water or an organicsolvent, which may be employed alone or in combination with each other.The ratio between water and the organic solvent when being employed incombination (water/organic solvent: weight ratio) may vary from 1 to100%, and is preferably 1 to about 30%. While said organic solvent isnot limited particularly as long as it can dissolve a water-insolublematerial, it may for example be a lower alcohol such as methyl alcohol,ethyl alcohol, isopropyl alcohol and n-butyl alcohol, etc., a loweralkanone such as acetone, etc., as well as acetonitrile, chloroform,methylene chloride and the like. Among those listed above, a loweralcohol is preferred, with ethyl alcohol and isopropyl alcohol beingespecially preferred. Water and a mixture of water and an organicsolvent are employed preferably as solvents for a coating. In such acase, an acid such as tartaric acid, citric acid, succinic acid, fumaricacid and maleic acid may be added to the coating solution for thepurpose of stabilizing the coating solution.

[1137] An operation when the coating is effected by a spray coating, astandard coating method can be employed, and typically a core is sprayedwith a coating by a fluidized bed coating method and a pan coatingmethod. During this process, a lubricant such as talc, titanium oxide,magnesium stearate, calcium stearate and light silicic anhydride, etc.and a plasticizer such as glycerin fatty acid ester, hardened castoroil, triethyl citrate, cetyl alcohol and stearyl alcohol, etc. may alsobe added.

[1138] After coating with the coating agent, an antistatic agent such asa talc may also be incorporated if necessary.

[1139] An instantaneous release formulation may be a liquid (solution,suspension, emulsion, etc.) or a solid (particle, pill, tablet, etc.).While an oral formulation and a parenteral formulation such as aninjection formulation may be employed, an oral formulation is preferred.

[1140] An instantaneous release formulation may usually contain, acarrier, additive and excipient (hereinafter sometimes abbreviated asexcipient) which are employed customarily in the pharmaceutical field,in addition to a medicament which is an active ingredient. Such aformulation excipient is not limited particularly as long as it is anexcipient employed usually as a formulation excipient. For example, anexcipient for an oral solid formulation may be lactose, starch, cornstarch, crystalline cellulose (Asahi Kasei, Avicel PH101 and the like),powder sugar, granulated sugar, mannitol, light silicic anhydride,magnesium carbonate, calcium carbonate, L-cysteine and the like, withcorn starch and mannitol being preferred. Any of these excipients may beemployed alone or in combination with each other. The amount of anexcipient may for example be about 4.5 to about 99.4 w/w %, preferablyabout 20 to about 98.5 w/w %, more preferably about 30 to about 97 w/w%, based on the entire amount of an instantaneous release formulation.

[1141] The medicament content in an instantaneous release formulationmay be selected within the range from about 0.5 to about 95%, preferablyabout 1 to about 60%, based on the entire amount of an instantaneousrelease formulation.

[1142] An oral solid instantaneous release formulation contains adisintegrant in addition to the ingredients described above. Such adisintegrant may for example be calcium carboxymethyl cellulose(GOTOKUYAKUHIN, ECG505), sodium croscarmellose (for example, AsahiKasei, Ac-Di-Sol), crospovidone (for example, BASF, COLIDON CL),low-substituted hydroxypropyl cellulose (SHINETSU KAGAKU), carboxymethylstarch (MATSUTANI KAGAKU), sodium carboxymethyl starch (KIMURASANGYO,EXORITAB), partial a starch (Asahi Kasei, PCS) and the like, any ofwhich may for example be brought into contact with water to effect waterabsorption or swelling, or to make a channel between a core-formingactive ingredient and an excipient, whereby, disintegrating a granule.Any of these disintegrants may be employed alone or in combination witheach other. While the amount of a disintegrant to be incorporated may beselected appropriately based on the type and the amount of themedicament employed and the preparation design for releasing, it may forexample be about 0.05 to about 30 w/w %, preferably about 0.5 to about15 w/w % based on the entire amount of an instantaneous releaseformulation.

[1143] An oral solid instantaneous release formulation containsadditives employed customarily in a solid formulation if desired inaddition to the components described above. Such additives may forexample be binders (for example, sucrose, gelatin, powdery gum arabic,methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, carboxymethyl cellulose, polyvinylpyrrolidone, pulluran,dextrin, etc.), lubricants (polyethylene glycol, magnesium stearate,talc, light silicic anhydride (for example, aerosil (NIPPON AEROSIL)),surfactants (for example, anionic surfactants such as sodiumalkylsulfate, nonionic surfactants such as polyoxyethylene fatty acidester and polyoxyethylene sorbitan fatty acid ester, polyoxyethylenecastor oil derivatives, etc.), colorants (for example, tar-basedcolorants, caramel, red ocher, titanium oxide, ribofravin, etc.), ifnecessary together with seasonings (for example, sweetener and flavor),adsorbents, preservatives, wetting agents, antistatic agents and thelike. As a stabilizer, an organic acid such as tartaric acid, citricacid, succinic acid and fumaric acid may also be added.

[1144] Binders described above are preferably hydroxypropyl cellulose,polyethylene glycol and polyvinylpyrrolidone, etc.

[1145] An instantaneous formulation can be prepared based on an ordinaryformulation technology by mixing the components described above andkneading if necessary and then molding. Such a mixing may beaccomplished by an ordinary method, such as mixing and kneading.Typically, when an instantaneous release formulation is formed as aparticle, then a method similar to that for preparing a core of asustained release formulation described above is employed to mix thematerials using a vertical granulator, multi-purpose kneader (HATAKETEKKOSHO), fluidized bed granulator FD-5S (Powrex Corporation) and thelike, after which a granulation is effected using a wet extrusiongranulation or a fluidized bed granulation.

[1146] Each of an instantaneous release formulation and a sustainedrelease formulation thus obtained may be formulated separately by astandard method as it is or in combination with an excipient properlyand then provided as a final formulation for simultaneous administrationor intermittent sequential administration, or the both may be formulatedin a single oral formulation (e.g., granule., fine powder, tablet,capsule, etc.) as they are or in combination with an excipient properly.The both formulation may be formulated also as granules or fine powders,which are then filled in a single capsule for oral administration.

[1147] [3] Sublingual, buccal or instant oral disintegrationformulations and method for producing the same

[1148] Any of sublingual, buccal or instant oral disintegrationformulations may be a solid formulation such as a tablet, etc., or maybe an oral mucosa plaster (film).

[1149] Each of sublingual, buccal or instant oral disintegrationformulations is preferably a formulation containing an inventivecompound or a concomitant medicament together with an excipient. Anauxiliary agent may also be contained such as a lubricant, osmoticagent, hydrophilic carrier, water-dispersible polymer and stabilizer.For the purpose of promoting the absorption and enhancing thebioavailability, β-cyclodextrin or β-cyclodextrin derivatives (e.g.,hydroxypropyl-β-cyclodextrin, etc.), etc. may also be. contained.

[1150] Such an excipient may for example be lactose, sugar, D-mannitol,starch, crystalline cellulose, light silicic anhydride and the like. Alubricant may for example be magnesium stearate, calcium stearate, talc,colloidal silica and the like, with magnesium stearate and colloidalsilica being preferred. An osmotic agent may for example be sodiumchloride, glucose, fructose, mannitol, sorbitol, lactose, saccharose,glycerin and urea, with mannitol being preferred especially. Ahydrophilic carrier may for example be a swelling hydrophilic carriersuch as a crystalline cellulose, ethyl cellulose, crosslinked polyvinylpyrrolidone, light silicic anhydride, silicic acid, dicalcium phosphate,calcium carbonate and the like, with a crystalline cellulose (e.g.,microcrystalline cellulose) being preferred. A water-dispersible polymermay for example be a gum (e.g., tragacanth gum, acacia gum, guar gum),alginate (e.g., sodium alginate), cellulose derivative (e.g., methylcellulose, carboxymethyl cellulose, hydroxymethyl cellulose,hydroxypropyl cellulose, hydroxypropylmethyl cellulose), gelatin,water-soluble starch, polyacrylic acid (e.g., carbomer), polymethacrylicacid, polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone,polycarbophil, ascorbate palmitate ester and the like, withhydroxypropylmethyl cellulose, polyacrylic acid, alginate, gelatin,carboxymethyl cellulose, polyvinylpyrrolidone and polyethylene glycol,etc. being preferred. Hydroxypropylmethyl cellulose is especiallypreferred. A stabilizer may for example be cysteine, thiosorbitol,tartaric acid, citric acid, sodium carbonate, ascorbic acid, glycine andsodium sulfite, with citric acid and ascorbic acid being preferredespecially.

[1151] Each of sublingual, buccal or instant oral disintegrationformulations can be produced by mixing an inventive compound orconcomitant medicament with an excipient by a method known per se. Ifdesired, an auxiliary agent described above, such as lubricant, osmoticagent, hydrophilic carrier, water-dispersible polymer, stabilizer,colorant, sweeteners and preservative, may also be incorporated. Aftermixing the components described above simultaneously or at a certaintime interval, the mixture is compressed and molded into each ofsublingual, buccal or instant oral disintegration formulations. For thepurpose of obtaining a suitable hardness, a solvent such as water andalcohol may be employed to hydrate the mixture before or after thetablet impaction, and then dried finally.

[1152] When an oral mucosa plaster (film) is to be molded, an inventivecompound or concomitant medicament and a water-dispersible polymer(preferably, hydroxypropyl cellulose, hydroxypropylmethyl cellulose) andexcipient described above are dissolved in a solvent such as water, andthen the resultant solution is casted into a film. Additives may also beadded such as plasticizers, stabilizers, antioxidants, preservatives,colorants, buffering agents and sweeteners. A glycol such aspolyethylene glycol or propylene glycol may be added for the purpose ofimparting a film with an appropriate elasticity, and a bioadhesivepolymer (e.g., polycarbophile, carbopol) may be added for the purpose ofenhancing the adhesion of the film to the oral mucosal lining. Thecasting may be accomplished by pouring a solution onto a non-adhesivesurface, spreading the solution using a coater such as a doctor blade,etc. into a uniform thickness (preferably about 10 to 1000 microns), andthen drying the solution to form a film. The film thus formed is driedat room temperature or with arming, and then cut into pieces each havinga desired surface area.

[1153] A preferred instant oral disintegration formulation may forexample be a rapid diffusion formulation in the form of a solid networkconsisting of an inventive compound or concomitant medicament togetherwith a water-soluble or water-diffusible carrier which is inert to theinventive compound or concomitant medicament. Said network is obtainedby sublimating a solvent from a solid composition consisting of asolution of an inventive compound or concomitant medicament in asuitable solvent.

[1154] In addition to an inventive compound or concomitant medicament, amatrix-forming agent and a secondary component are contained preferablyin the composition of said instant oral disintegration formulation.

[1155] Said matrix-forming agents may for example be an animal orvegetable protein such as a gelatin, dextrin and soybean, wheat andpsyllium seed proteins; a gummy material such as gum arabic, guar gum,agar and xanthane gum; polysaccharide; alginate; carboxymethylcellulose; carrageenan; dextran; pectin; synthetic polymer such aspolyvinylpyrrolidone; a material derived from a gelatin-gum arabiccomplex. Those which are also included are saccharides such as mannitol,dextrose, lactose, galactose and trehalose, etc.; cyclic saccharidessuch as cyclodextrin, etc.; inorganic salts such as sodium phosphate,sodium chloride and aluminum silicate, etc.; amino acids having 2 to 12carbon atoms such as glycine, L-alanine, L-aspartic acid, L-glutamicacid, L-hydroxyproline, L-isoleucine, L-leucine and L-phenylalanine,etc.

[1156] One or more matrix-forming agents may be introduced into asolution or suspension before solidification. Such a matrix-formingagent may be present in addition to a surfactant, or may be present inthe absence of the surfactant. The matrix-forming agent serves not onlyto form a matrix itself, but also to aid in maintaining the inventivecompound or concomitant medicament as being diffused in the solution orsuspension.

[1157] A secondary agent may be contained in a composition such as apreservative, antioxidant, surfactant, thickening agent, colorant, pHmodifier, flavor, sweetener or taste masking agent, etc. A suitablecolorant may for example be iron oxide red, black and yellow, FD&C dyesavailable from ERIS AND EVERALD such as FD&C Blue No.2 and FD&C RedNo.40. A suitable flavor may for example be mint, raspberry, licorice,orange, lemon, grape fruit, caramel, vanilla, cherry and grape flavor aswell as a combination thereof. A suitable pH modifier may for example becitric acid, tartaric acid, phosphoric acid, hydrochloric acid andmaleic acid. A suitable sweetener may for example be aspartame,acesulfame K and thaumatine. A suitable taste masking agent may forexample be sodium bicarbonate, ion exchange resin, cyclodextrininclusion compound, adsorbent and microencapsulated apomorphine.

[1158] A formulation contains an inventive compound or concomitantmedicament in an amount usually of about 0.1 to about 50% by weight,preferably about 0.1 to about 30% by weight, and is preferably aformulation (sublingual or buccal formulation described above) whichallows 90% or more of the inventive compound or concomitant medicamentto be dissolved. (in water) within a time period of about 1 to about 60minutes, preferably about 1 minutes to about 15 minutes, more preferablyabout 2 minutes to about 5 minutes, or a instant oral disintegrationformulation which disintegrates within about 1 to about 60 seconds,preferably about 1 to about 30 seconds, more preferably about 1 to about10 seconds after being placed in the oral cavity.

[1159] The amount of an excipient described above based on the entireformulation is about 10 to about 99% by weight, preferably about 30 toabout 90% by weight. The amount of β-cyclodextrin or β-cyclodextrinderivative based on the entire formulation is about 0 to about 30% byweight. The amount of a lubricant based on the entire formulation isabout 0.1 to about 10% by weight, preferably about 1 to about 5% byweight. The amount of an osmotic agent based on the entire formulationis about 0.01 to about 90% by weight, preferably about 10 to about 70%by weight. The amount of a hydrophilic carrier based on the entireformulation is about 0.1 to about 50% by weight, preferably about 10 toabout 30% by weight. The amount of a water-dispersible polymer based onthe entire formulation is about 0.1 to about 30% by weight, preferablyabout 10 to about 25% by weight. The amount of a stabilizer based on theentire formulation is about 0.1 to about 10% by weight, preferably about1 to about 5% by weight. The formulation described above may furthercontain additives if desired such as colorants, sweeteners andpreservatives, etc.

[1160] While the dose of an inventive concomitant preparation may varydepending on the type of the inventive compound, the subject's age, bodyweight, condition, and the dosage form as well as administration modeand duration, the daily dose for example in a patient having a breastcancer (adult, body weight: about 60 kg) is about 0.01 to about 1000mg/kg as an inventive compound and concomitant medicament, preferablyabout 0.01 to about 100 mg/kg, more preferably about 0.1 to about 100mg/kg, particularly about 0.1 to about 50 mg/kg, especially about 1.5 toabout 30 mg/kg, which is given intravenously at once or in severalportions. It is a matter of course that the dose may vary depending onvarious factors as described above, and a less amount may sometimes besufficient and an excessive amount should sometimes be required.

[1161] A concomitant medicament may be employed in any amount within therange causing no problematic side effects. The daily dose of aconcomitant medicament is not limited particularly and may varydepending on the severity of the disease, the subject's age, sex, bodyweight and susceptibility as well as time and interval of theadministration and the characteristics, preparation, type and activeingredient of the pharmaceutical formulation, and the daily oral doseper kg body weight in a mammal is about 0.001 to 2000 mg, preferablyabout 0.01 to 500 mg, more preferably about 0.1 to about 100 mg asmedicaments, which is given usually in 1 to 4 portions.

[1162] When the inventive concomitant preparation is administered, itmay be administered at the same time, but it is also possible that theconcomitant medicament is first administered and then the inventivecompound is administered, or that the inventive compound is firstadministered and then the concomitant medicament is administered. Whensuch an intermittent administration is employed, the time interval mayvary depending on the active ingredient administered, the dosage formand the administration mode, and when the concomitant medicament isfirst administered, the inventive compound may be administered within 1minute to 3 days, preferably 10 minutes to 1 day, more preferably 15minutes to 1 hour after the administration of the concomitantmedicament. When the inventive compound is first administered, then theconcomitant medicament may be administered within 1 minutes to 1 day,preferably 10 minutes to 6 hours, more preferably 15 minutes to 1 hourafter the administration of the inventive compound.

[1163] The present invention is further detailed in the followingReference Examples, Examples, Formulation Examples and ExperimentExamples, any of which serves only a practice and is not intended torestrict the invention and can be modified without departing from thescope of the invention.

[1164] In the following Reference Examples and Examples, the term “roomtemperature ” usually means a temperature from about 10 to about 35° C.A % means a mol/mol % when employed for a yield and a % by volume whenemployed for a chromatographic solvent, and otherwise it is a % byweight. A basic silica gel employed was NH-DM1020 manufactured by FUJISILYSIA CHEMICAL LTD. Any unidentifiable broad peak such as those of OHand NH protons in each proton NMR spectrum are not included in the data.

[1165] Abbreviations shown below are employed here.

[1166] s: Singlet

[1167] d: Doublet

[1168] t: Triplet

[1169] q: Quartet

[1170] m: Multiplet

[1171] br: Broad

[1172] J: Coupling constant

[1173] Hz: Hertz

[1174] CDCl₃: chloroform-d

[1175] DMSO-d₆: dimethylsulfoxide-d₆

[1176]¹H NMR: Proton nuclear magnetic resonance

[1177] A transformant Escherichia colt BL21/pPDE4D3 obtained inExperiment Example 1 described below was deposited on Mar. 8, 2000 toNational Institute of Bioscience and Human-Technology Agency ofIndustrial Science and. Technology (NIBH) under the deposition No.FERMBP-7075 and on Feb. 24, 2000 to Institution for Fermentation, Osaka(IFO) under the deposition No.IFO 16383.

[1178] The gene engineering operations employing Escherichia coli was inaccordance with Molecular Cloning.

[1179] The Sequence ID Nos. in the sequence listing in thisspecification indicate the following sequences.

[1180] [Sequence ID No.1]

[1181] Sequence ID No.1 indicates the base sequence of a primer employedin Experiment Example 1.

[1182] [Sequence ID No.2]

[1183] Sequence ID No.2 indicates the base sequence of a primer employedin Experiment Example.

[1184] [Sequence ID No.3]

[1185] Sequence ID No.3 indicates the cDNA base sequence possessed byEscherichia coli BL21/pPDE4D3 obtained in Experiment Example 1.

[1186] [Sequence ID No.4]

[1187] Sequence ID No.4 indicates the amino acid sequence encoded by thecDNA base sequence possessed by Escherichia coli BL21/pPDE4D3 obtainedin Experiment Example 1.

EXAMPLES Reference Example 1

[1188] 4-Hydroxy-3-methoxy-5-(2-methyl-2-propenyl)benzaldehyde

[1189] To a solution of vanillin (25.6 g, 0.168 mol) inN,N-dimethylformamide (150 mL), 3-chloro-2-methyl-1-propene (19.9 mL,0.202 mol) and potassium carbonate (30.2 g, 0.219 mol) was added and themixture was stirred at 75° C. for 2.5 hours under nitrogen atmosphere.Water was added to the reaction mixture and the mixture was extractedthree times with ethyl acetate. The combined organic layer was washedtwice with water, and then concentrated under reduced pressure. Theresidue was subjected to a column chromatography on a silica gel(hexane/ethyl acetate, 5:1) to obtain3-methoxy-4-(2-methyl-2-propenyloxy)benzaldehyde (35.4 g) as an oil.

[1190] This 34.3 g of the material was dissolved in N,N-diethylaniline(80 mL), and stirred at 200° C. for 5 hours under nitrogen atmosphere.The reaction mixture was dissolved in diisopropyl ether, washed with 1 Mhydrochloric acid (twice) and brine, dried over magnesium sulfate,treated with activated charcoal, filtered, and concentrated underreduced pressure. The residue was crystallized from diisopropylether-hexane to obtain the title compound (27.1 g, yield: 79%).

[1191] Melting point: 53-54° C.

[1192]¹H NMR (CDCl₃) δ1.75 (3H, s), 3.42 (2H, s), 3.97 (3H, s),4.69-4.75 (1H, m), 4.82-4.97 (1H, m), 6.31 (1H, s), 7.31 (2H, s), 9.81(1H, s).

Reference Example 2

[1193] 4-Hydroxy-3-methoxy-5(2-methyl-2-propenyl)benzaldehyde

[1194] To a solution of 3-ethoxy-4-hydroxybenzaldehyde (25.6 g, 0.154mol) in N,N-dimethylformamide (150 mL), 3-chloro-2-methyl-1-propene(16.7 mL, 0.169 mol) and potassium carbonate (24.5 g, 0.177 mol) wereadded, and the mixture was stirred at 80° C. for 3 hours under nitrogenatmosphere. Water was added to the reaction mixture and the reactionmixture was extracted twice with ethyl acetate. The combined organiclayer was washed twice with water, and then concentrated under reducedpressure to obtain 3-ethoxy-4-(2-methyl-2-propenyloxy)benzaldehyde (35.5g) as an oil.

[1195] This was dissolved in N,N-diethylaniline (25 mL), and stirred at210° C. for 5 hours under nitrogen atmosphere. The reaction mixture wasdissolved in ethyl acetate, washed twice with 1 M hydrochloric acid andtwice with water, and then concentrated under reduced pressure. Theresidue was crystallized from diisopropyl ether-hexane to obtain thetitle compound (26.7 g, yield: 79%).

[1196] Melting Point: 85-86° C.

[1197]¹H NMR (CDCl₃) δ1.48 (3H, t, J=7.0 Hz), 1.75 (3H, s), 3.42 (2H,s), 4.20 (2H, q, J=7.0 Hz), 4.68-4.73 (1H, m), 4.82-4.87 (1H, m), 6.34(1H, s), 7.29 (2H, s), 9.80 (1H, s).

Reference Example 3

[1198] 2,3-Dihydro-7-methoxy-2,2-dimethyl-5-benzofurancarboxaldehyde

[1199] To a solution of4-hydroxy-3-methoxy-5-(2-methyl-2-propenyl)benzaldehyde (26.2 g, 0.127mol) in toluene (130 mL), boron trifluoride diethyl ether complex (17.2mL, 0.140 mol) was added, and the mixture was stirred at 110° C. for 1hour.

[1200] The reaction mixture was washed with water and saturated sodiumhydrogen carbonate, dried through sodium sulfate and a silica gel(eluted with hexane/ethyl acetate 3:1), and then concentrated underreduce pressure. The residue was crystallized from diisopropylether-hexane to obtain the title compound (17.1 g, yield: 65%).

[1201] Melting point: 58-59° C.

[1202]¹H NMR (CDCl₃) δ1.56 (6H, s), 3.11 (2H, s), 3.94 (3H, s),7.28-7.35 (2H, m), 9.80 (1H, s).

[1203] (Alternative Synthetic Method)

[1204] A suspension of4-hydroxy-3-methoxy-5-(2-methyl-2-propenyl)benzaldehyde (88.4 g, 0.429mol) and Amberlyst 15 (trade name) (17 g) in toluene (300 mL) wasstirred at 100° C. for 1.5 hours. The reaction mixture was filtered, andwashed with ethyl acetate. The filtrate was washed with 0.5 M aqueoussolution of sodium hydroxide and water (twice), and concentrated underreduced pressure. The residue was crystallized from diisopropylether-hexane to obtain the title compound (72.1 g, yield: 82%).

Reference Example 4

[1205] 7-Ethoxy-2,3-dihydro-2,2-dimethyl-5-benzofurancarboxaldehyde

[1206] To a solution of3-ethoxy-4-hydroxy-5-(2-methyl-2-propenyl)benzaldehyde (28.9 g, 0.131mol) in toluene (150 mL), boron trifluoride diethyl ether complex (17.8mL, 0.145 mol) was added, and the mixture was stirred at 100° C. for 1hour. The reaction mixture was washed with water, saturated aqueoussolution of sodium hydrogen carbonate and brine, dried through sodiumsulfate and a silica gel (eluted with hexane/ethyl acetate 5:1), andthen concentrated under reduced pressure to obtain the title compound(26.8 g, yield: 93%).

[1207] Melting point: 33-36° C.

[1208]¹H NMR (CDCl₃) δ1.47 (3H, t, J=7.0 Hz), 1.56 (6H, s), 3.09 (2H,s), 4.19 (2H, q, J=7.0 Hz), 7.26-7.35 (2H, m), 9.78 (1H, s).

Reference Example 5

[1209]2,3-Dihydro-7-methoxy-2,2-dimethyl-5-(2-methyl-1-propenyl)benzofuran

[1210] To a suspension of2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofurancarboxaldehyde (1.50 g,7.27 mmol) and isopropyltriphenylphosphonium iodide (3.77 g, 8.73 mmol)in tetrahydrofuran (20 mL), sodium hydride (66% suspension in oil) (397mg, 11 mmol) was added, and the mixture was heated under reflux for 1.5hours. The reaction mixture was poured into a 10% aqueous solution ofammonium chloride, and extracted twice with ethyl acetate. The combinedorganic layer was washed with water and brine, dried over magnesiumsulfate, filtered, and then concentrated under reduced pressure. Theresidue was subjected to a column chromatography on a silica gel(hexane/ethyl acetate, 50:1 followed by 30:1) to obtain the titlecompound (1.22 g, yield: 72%). An oil.

[1211]¹H NMR (CDCl₃) δ1.51 (6H, s), 1.867 (3H, d, J=1.4 Hz), 1.874 (3H,d, J=1.4 Hz), 3.02 (2H, s), 3.85 (3H, s), 6.20 (1H, s), 6.61 (1H, s),6.65 (1H, s).

[1212] (Alternative synthetic method)

[1213] To a solution of guaiacol (124 g, 1.00 mol) inN,N-dimethylformamide (500 mL), 3-chloro-2-methyl-1-propene (128 mL,1.30 mol) and potassium carbonate (166 g, 1.20 mol) were added, and themixture was stirred at 80° C. for 5 hours under nitrogen atmosphere.Water was added to the reaction mixture and the mixture was extractedtwice with hexane. The combined organic layer was washed each twice with0.5 M aqueous solution of sodium hydroxide and water, and thenconcentrated under reduced pressure to obtain1-methoxy-2-[(2-methyl-2-propenyl)oxy]benzene (178 g) as an oil.

[1214] This was dissolved in N,N-diethylaniline (250 mL), and stirred at205° C. for 5 hours under nitrogen atmosphere. The reaction mixture wascooled with ice, combined with 2 M hydrochloric acid (850 mL), andextracted with ethyl acetate. The organic layer was washed twice withwater, and concentrated under reduced pressure to obtain2-methoxy-6-(2-methyl-2-propenyl)phenol (178 g) as an oil.

[1215] This was dissolved in N,N-dimethylformamide (600 ml).3-chloro-2-methyl-1-propene (128 mL, 1.30 mol) and potassium carbonate(166 g, 1.20 mol) were added to the mixture and the mixture was stirredat 80° C. for 7 hours under nitrogen atmosphere. Water was added to thereaction mixture and the mixture was extracted twice with hexane. Thecombined organic layer was washed each twice with water, an aqueoussolution of sodium hydroxide and water, and then concentrated underreduced pressure to obtain1-methoxy-3-(2-methyl-2-propenyl)-2-[(2-methyl-2-propenyl)oxy]benzene(231 g) as an oil.

[1216] This was dissolved in N,N-diethylaniline (250 mL), and stirred at205° C. for 5 hours under nitrogen atmosphere. The reaction mixture wascooled with ice, combined with 2 M hydrochloric acid (850 mL), andextracted twice with ethyl acetate. The combined organic layer waswashed twice with water, and concentrated under reduced pressure. Theresidue was distilled under reduced pressure to obtain2-methoxy-4,6-bis(2-methyl-2-propenyl)phenol (186 g, yield: 80%).

[1217] Boiling point: 104-115° C./0.11 kPa (0.8 mmHg).

[1218] 164 g (0.706 mol) of this material was dissolved in ethanol (300mL). conc. hydrochloric acid (75 mL) and ethanol (75 mL) were added tothe reaction mixture and the mixture was heated under reflux for 13hours. The reaction mixture was combined with hexane and water, andthe-organic layer was separated, and then the aqueous layer wasextracted with hexane. The combined organic layer was washed with water,5 M aqueous solution of sodium hydroxide and water (twice), treated withactivated charcoal, filtered, and then concentrated under reducedpressure to obtain the title compound (163 g) as an oil. This was usedin the next reaction without further purification.

Reference Example 6

[1219]7-Ethoxy-2,3-dihydro-2,2-dimethyl-5-(2-methyl-1-propenyl)benzofuran

[1220] The title compound was obtained from7-ethoxy-2,3-dihydro-2,2-dimethyl-5-benzofurancarboxaldehyde by themethod similar to that in Reference Example 5. Yield: 91%. An oil.

[1221]¹H NMR (CDCl₃) δ1.42 (3H, t, J=6.9 Hz), 1.51 (6H, s), 1.83-1.89(6H, m), 3.00 (2H, s), 4.11 (2H, q, J=6.9 Hz), 6.18 (1H, br s), 6.61(1H, s), 6.64 (1H, s).

Reference Example 7

[1222]1-(2,3-Dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-2-methyl-1-propanol

[1223] To a 15% solution of isopropylmagnesium bromide/tetrahydrofuran(101 g, 0.10 mol), a solution of2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofurancarboxaldehyde (20.2 g,97.9 mmol) in tetrahydrofuran (100 mL) was added dropwise, and themixture was stirred at room temperature for 40 minutes. The reactionmixture was poured into a saturated aqueous solution of ammoniumchloride, and extracted twice with ethyl acetate. The combined organiclayer was washed twice with water, treated with activated charcoal,filtered, and concentrated under reduced pressure. The residue wasrecrystallized from ethyl acetate-hexane to obtain the title compound(17.4 g, yield: 71%).

[1224] Melting point: 113-116° C.

[1225]¹H NMR (CDCl₃) δ0.78 (3H, d, J=7.0 Hz), 1.03 (3H, d, J=6.6 Hz),1.51 (6H, s), 1.92 (1H, sixtet, J=6.9 Hz), 3.02 (2H, s), 3.87 (3H, s),4.23 (1H, d, J=7.6 Hz), 6.71 (2H, s).

Reference Example 8

[1226]1-(2,3-Dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-2-methyl-1-propoylacetate

[1227] To a solution of1-(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-2-methyl-1-propanol(937 mg, 3.74 mol) in pyridine (5 mL), acetic anhydride (0.35 mL, 3.7mmol) was added dropwise with cooling in ice, and the mixture wasstirred at 60° C. for 2 hours. The reaction mixture was dissolved indiisopropyl ether, washed with water, 1 M hydrochloric acid (twice), asaturated aqueous solution of sodium hydrogen carbonate and water, andthen concentrated under reduced pressure. The residue was subjected to acolumn chromatography on a silica gel (hexane/ethyl acetate, 20:1followed by 10:1) to obtain the title compound (915 mg, yield: 84%).

[1228] An oil.

[1229]¹H NMR (CDCl₃) δ0.78 (3H, d, J=6.6 Hz), 0.98 (3H, d, J=6.6 Hz),1.50 (6H, s), 1.95-2.17 (1H, m), 2.06 (3H, s), 3.01 (2H, s), 3.86 (3H,s), 5.35 (1H, d, J=8.4 Hz), 6.66 (1H, s), 6.71 (1H, s).

Reference Example 9

[1230]2,3-Dihydro-7-methoxy-2,2-dimethyl-5-(2-methyl-2-propenyl)benzofuran

[1231] To a solution of guaiacol (12.5 g, 0.101 mol) in dichloromethane(50 mL), a solution of bromine (5.3 mL, 0.10 mol) in dichloromethane (10mL) was added dropwise at −10° C. over 50 minutes, and the mixture wasstirred at room temperature for 1 hour. The reaction mixture wascombined with water, the organic layer was separated, and the aqueouslayer was extracted with dichloromethane. The combined organic layer waswashed with a saturated aqueous solution of sodium hydrogen carbonateand brine, dried over magnesium sulfate, filtered, and concentratedunder reduced pressure to obtain an oil.

[1232] This was dissolved in N,N-dimethylformamide (80 mL).3-Chloro-2-methyl-1-propene (11 mL, 0.11 mol) and potassium carbonate(16.6 g, 0.120 mol) were added to the mixture and the mixture wasstirred at 80° C. for 3 hours under nitrogen atmosphere. The reactionmixture was combined with water, and extracted twice with ethylacetate/hexane (1:1). The combined organic layer was washed with 0.5 Maqueous solution of sodium hydroxide and water (twice), treated withactivated charcoal, filtered, and concentrated under reduced pressure toobtain an oil.

[1233] This was dissolved in N,N-diethylaniline (20 mL), and stirred at205° C. for 5 hours under nitrogen atmosphere. The reaction mixture wasdissolved in diisopropyl ether, washed with 1 M hydrochloric acid(twice) and water, treated with activated charcoal, filtered, andconcentrated under reduced pressure to obtain an oil.

[1234] This was dissolved in ethanol (40 mL). Conc. hydrochloric acid(10 mL) and ethanol (10 mL) were added to the mixture and the mixturewas heated under reflux for 2.5 hours. The reaction mixture was combinedwith hexane, the organic layer was separated, and the aqueous layer wasextracted with hexane and diisopropyl ether. The combined organic layerwas washed with 2 M aqueous solution of sodium hydroxide (twice) andwater, and concentrated under reduced pressure. The residue wassubjected to a column chromatography on a silica gel (hexane/ethylacetate, 20:1) to obtain an oil (15.7 g).

[1235] 2.57 g of this material was dissolved in tetrahydrofuran (10 mL),a 1.6 M solution of n-butyllithium/hexane (7.5 mL, 12 mmol) was addeddropwise to the mixture at −40° C., and the mixture was stirred at thesame temperature for 1 hour. To this, copper (I) iodide (1.14 g, 5.99mmol) was added, and the mixture was stirred at −40° C. for 20 minutes.To the resultant mixture, 3-chloro-2-methyl-1-propene (1.1 mL, 11 mmol)was added dropwise, and the mixture was stirred at room temperature for1 hour. The reaction mixture was poured into ice water, the insolubleswere filtered off, and washed with ethyl acetate. The organic layer wasseparated, and the aqueous layer was extracted with ethyl acetate. Thecombined organic layer was washed with water and brine, dried overmagnesium sulfate, filtered, and concentrated under reduced pressure.The residue was subjected to a column chromatography on a silica gel(hexane/ethyl acetate, 50:1) to obtain the title compound (1.77 g,yield: 46%).

[1236] An oil.

[1237]¹H NMR (CDCl₃) δ1.50 (6H, s), 1.69 (3H, s), 3.00 (2H, s), 3.24(2H, s), 3.85 (3H, s), 4.74 (1H, br s), 4.79 (1H, br s), 6.55 (1H, s),6.59 (1H, s).

Reference Example 10

[1238]6-Ethoxy-1,2,3,4,8,9-hexahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinoline

[1239] To a solution of6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinoline(2.27 g, 6.50 mmol) in methanol (30 mL), 0.8 M solution of hydrogenchloride/methanol (9.7 mL) was added dropwise. The resultant mixture wascooled with ice, treated portionwise with sodium borohydride (90%) (0.28g, 7.8 mmol), and stirred at room temperature for 10 minutes. Thereaction mixture was combined with water, and extracted twice with ethylacetate. The combined organic layer was washed with water and brine,dried over sodium sulfate, filtered, and concentrated under reducedpressure to obtain the title compound (2.20 g, yield: 96%).

[1240] A gum.

[1241]¹H NMR (CDCl₃) δ1.16 (3H, s), 1.21 (3H, s), 1.24 (3H, s), 1.34(3H, s), 1.43 (3H, t, J=7.0 Hz), 1.76 (1H, d, J=15.7 Hz), 2.43 (1H, d,J=15.7 Hz), 2.54 (1H, d, J=15.0 Hz), 2.80 (1H, d, J=15.0 Hz), 4.11 (2H,q, J=7.0 Hz), 4.93 (1H, s), 6.49 (1H, s), 7.16-7.38 (5H, m).

Reference Example 11

[1242]1,2,3,4,8,9-Hexahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinoline

[1243] The title compound was obtained from3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolineby the method similar to that in Reference Example 10.

[1244] Quantitative Amorphous.

[1245]¹H NMR (CDCl₃) δ1.17 (3H, s), 1.21 (3H, s), 1.24 (3H, s), 1.34(3H, s), 1.76 (1H, d, J=15.8 Hz), 2.44 (1H, d, J=15.8 Hz), 2.55 (1H, d,J=15.0 Hz), 2.81 (1H, d, J=15.0 Hz), 3.86 (3H, s), 4.93 (1H, s), 6.49(1H, s), 7.13-7.38 (5H, m).

Reference Example 12

[1246]4-(6-Ethoxy-1,2,3,4,8,9-hexahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide

[1247] The title compound was obtained from4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamideby the method similar to that in Reference Example 10. Yield: 96%.

[1248] Melting point: 157-163° C. (ethyl acetate-hexane).

[1249]¹H NMR (CDCl₃) δ1.17 (3H, s), 1.22 (3H, s), 1.24 (3H, s), 1.34(3H, s), 1.43 (3H, t, J=7.0 Hz), 1.76 (1H, d, J=15.5 Hz), 2.42 (1H, d,J=15.5 Hz), 2.54 (1H, d, J=15.4 Hz), 2.82 (1H, d, J=15.4 Hz), 4.11 (2H,q, J=7.0 Hz), 5.00 (1H, s), 5.45-6.40 (2H, m), 6.50 (1H, s), 7.33 (2H,d, J=8.2 Hz), 7.75 (2H, d, J=8.2 Hz).

Reference Example 13

[1250]3-(2,3-Dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-3-hydroxy-2,2-dimethylpropionicacid ethyl ester

[1251] To a solution of 1,1,1,3,3,3-hexamethyldisilazane (1.88 g, 11.6mmol) in tetrahydrofuran (40 mL), a 1.53 M solution ofn-butyllithium/hexane (7.61 mL, 11.6 mmol) was added dropwise at −78°C., and the mixture was stirred at the same temperature for 15 minutes.To the reaction mixture, a solution of ethyl isobutyrate (1.35 g, 11.6mmol) in tetrahydrofuran (1 mL) was added dropwise, and the mixture wasstirred with cooling in ice for 30 minutes. The reaction mixture wascooled at −78° C. again, and treated dropwise with a solution of2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofurancarboxaldehyde (2.00 g,9.70 mmol) in tetrahydrofuran (3 mL). The reaction mixture was stirredfor 1 hour, combined with an aqueous solution of ammonium chloride, andthen extracted with ethyl acetate. The extract was washed with water,and then concentrated under reduced pressure. The residue was subjectedto a column chromatography on a silica gel (hexane/ethyl acetate, 4:1 to13:7) to obtain the title compound (1.56 g, yield: 50%).

[1252] An oil.

[1253]¹H NMR (CDCl₃) δ1.11 (3H, s), 1.16 (3H, s), 1.28 (3H, t, J=7.2Hz), 1.50 (6H, s), 3.01 (2H, s), 3.86, (3H, s), 4.18 (2H, q, J=7.2 Hz),4.80 (1H, s), 6.70 (1H, s), 6.71 (1H, s).

[1254] (Alternative synthetic method)

[1255] To a mixture of zinc (powder, 11 g, 170 mmol) and toluene (300mL), a solution of2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofurancarboxaldehyde (17 g, 82mmol) and 2-bromoisobutyric acid ethyl ester. (35 g, 180 mmol) intoluene (300 mL) was added at 100° C. The reaction mixture was heatedunder reflux for 3 hours. The reaction mixture was cooled to roomtemperature, and then the insolubles were filtered off. The filtrate waswashed with 1 M hydrochloric acid and brine, dried over magnesiumsulfate, and then the solvent was distilled off under reduced pressure.The resultant residue was purified by a column chromatography on asilica gel (hexane/ethyl acetate, 5:1) to obtain the title compound (17g, yield: 62%).

Reference Example 14

[1256]3-(2,3-Dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-2,2-dimethylpropionicacid ethyl ester

[1257] To a solution of3-(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-3-hydroxy-2,2-dimethylpropionicacid ethyl ester (1.50 g, 4.65 mmol) and triethylsilane (0.817 mL, 5.12mmol) in dichloromethane (15 mL), boron trifluoride diethyl ethercomplex (0.648 mL, 5.12 mmol) was added with cooling in ice, and themixture was stirred with cooling in ice for 1 hour. The reaction mixturewas combined with a saturated aqueous solution of sodium hydrogencarbonate, and extracted with ethyl acetate. The extract was washed withwater, and concentrated under reduced pressure. The residue wassubjected to a column chromatography on a silica gel (hexane/ethylacetate, 9:1) to obtain the title compound (1.30 g, yield: 91%).

[1258] An oil.

[1259]¹H NMR (CDCl₃) δ1.17 (6H, s), 1.24 (3H, t, J=7.4 Hz), 1.49 (6H,s), 2.77 (2H, s), 2.98 (2H, s), 3.83 (3H, s), 4.11 (2H, q, J=7.4 Hz),6.49 (1H, s), 6.52 (1H, s).

Reference Example 15

[1260]3-(2,3-Dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-2,2-dimethylpropionicacid

[1261] To a solution of3-(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-2,2-dimethylpropionicacid ethyl ester (1.25 g, 4.08 mmol) in methanol (10 mL), 2 M aqueoussolution of sodium hydroxide was added, and the mixture was stirred for1.5 hours. The reaction mixture was acidified with 1 M hydrochloricacid, and extracted with ethyl acetate. The extract was washed withwater, and then concentrated under reduced pressure. The residue wassubjected to a column chromatography on a silica gel (hexane/ethylacetate, 3:2), and then recrystallized from hexane-ethyl acetate toobtain the title compound (0.87 g, yield: 69%).

[1262] Melting point: 88-89° C.

[1263]¹H NMR (CDCl₃) δ1.21 (6H, s), 1.50 (6H, s), 2.81 (2H, s), 2.99(2H, s), 3.82 (3H, s), 6.55 (2H, s).

Reference Example 16

[1264]N-[2-(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-1,1-dimethylethyl]-N′-phenylurea

[1265] To a solution of3-(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-2,2-dimethylpropionicacid (0.80 g, 2.87 mmol) and diphenylphosphoryl azide (0.650 mL, 3.01mmol) in toluene (5 mL), triethylamine (0.421 mL, 3.01 mmol) was added,and the mixture was stirred at 70° C. for 1 hour. The reaction mixturewas allowed to cool to room temperature. Aniline (0.275 mL, 3.01 mmol)was added to the mixture and the mixture was stirred at 80° C. for 1hour. The reaction mixture was diluted with ethyl acetate washed withwater followed by 1 M hydrochloric acid and water, and then concentratedunder reduced pressure. The residue was subjected to a columnchromatography on a silica gel (hexane/ethyl acetate, 7:3) to obtain thetitle compound (0.69 g, yield: 65%).

[1266] Amorphous.

[1267]¹H NMR (CDCl₃) δ1.34 (6H, s), 1.48 (6H, s), 2.96 (4H, s), 3.73(3H, s), 4.54 (1H, br s), 6.28 (1H, br s), 6.55 (2H, s), 7.04 (1H, t,J=7.0 Hz), 7.18-7.30 (4H, m).

Reference Example 17

[1268]N-[2-(2,3-Dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-1,1-dimethylethyl]-N′-(4-methoxyphenyl)urea

[1269] The title compound was obtained employing 4-methoxyaniline by themethod similar to that in Reference Example 16. Yield: 88%.

[1270] An oil.

[1271]¹H NMR (CDCl₃) δ1.32 (6H, s), 1.49 (6H, s), 2.93 (2H, s), 2.97(2H, s), 3.77 (3H, s), 3.78 (3H, s), 4.37 (1H, br s), 6.01 (1H, br s),6.53 (2H, s), 6.80 (2H, d, J=8.8 Hz), 7.04 (2H, d, J=8.8 Hz).

Reference Example 18

[1272]N-[2-(2,3-Dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-1,1-dimethylethyl]-1-piperidinecarboxamide

[1273] The title compound was obtained employing piperidine by themethod similar to that in Reference Example 16.

[1274] Melting Point: 133-134° C. (ethyl acetate-hexane).

[1275]¹H NMR (CDCl₃) δ1.34 (6H, s), 1.48-1.60 (6H, m), 1.50 (6H, s),2.93 (2H, s), 2.99 (2H, s), 3.21-3.28 (4H, m), 3.83 (3H, s), 4.11 (1H,br s), 6.53 (1H, s), 6.55 (1H, s).

Reference Example 19

[1276] Cyclohexyltriphenylphosphonium bromide

[1277] A mixture of cyclohexyl bromide (10.0 g, 61.3 mmol) andtriphenylphosphine (16.1 g, 61.3 mmol) was stirred at 140-150° C. for 72hours. The reaction solution was cooled, and then crystallized fromethyl acetate to obtain the title compound (19.1 g, yield: 73%). Thiswas used in the next reaction without further purification.

Reference Example 20

[1278]5-(Cyclohexylidenemethyl)-2,3-dihydro-7-methoxy-2,2-dimethylbenzofuran

[1279] A suspension of cyclohexyltriphenylphosphonium bromide (7.42 g,17.4 mmol) in tetrahydrofuran (70 mL) was cooled at −78° C., to this, a1.53 M solution of n-butyllithium in hexane (11.4 mL, 17.4 mmol) wasadded dropwise, and the mixture was stirred with cooling in ice for 1hour. To this,2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofurancarboxaldehyde (3.00 g,14.5 mmol) was added, and the mixture was allowed to stir with coolingin ice further for 1 hour. The reaction solution was combined withwater, and extracted with ethyl acetate. The extract was washed withwater, and then concentrated under reduced pressure. The residue wassubjected to a column chromatography on a silica gel (hexane/ethylacetate, 19:1) to obtain the title compound (0.87 g, yield: 22%).

[1280] An oil.

[1281]¹H NMR (CDCl₃) δ1.51 (6H, s), 1.59 (6H, br s), 2.20-2.26 (2H, m),2.35-2.42 (2H, m), 3.02 (2H, s), 3.85 (3H, s), 6.16 (1H, s), 6.58 (1H,s), 6.63 (1H, s).

Reference Example 21

[1282] 3-Formyl-α,α-dimethylbenzeneacetic acid ethyl ester

[1283] To a solution of 3-methylbenzeneacetic acid ethyl ester (10.0 g,56.1 mmol) in N,N-dimethylformamide (80 mL), sodium hydride (66%suspension in oil) (4.29 g, 118 mmol) was added with cooling in ice, andthe mixture was stirred at room temperature for 3 hours. A solution ofiodomethane (7.34 mL, 118 mmol) in N,N-dimethylformamide (20 mL) wasadded dropwise with cooling in ice, and the mixture was stirred at roomtemperature for 3.5 hours. Ice water was poured into the reactionmixture, and the mixture was extracted twice with ethyl acetate. Thecombined organic layer was washed with a dilute aqueous solution ofsodium chloride twice, and brine, dried over magnesium sulfate,filtered, and concentrated under reduced pressure to obtain the mixture(13.3 g) containing α,α,3-trimethylbenzeneacetic acid ethyl ester as anoil.

[1284] This was dissolved in ethyl acetate (100 mL). N-bromosuccinimide(10.5 g, 58.9 mmol and 2,2-azobis(isobutyronitrile) (92 mg, 561 mmol)were added to the mixture and the mixture was stirred at 60° C. for 9hours. Ice water was poured into the reaction mixture, and the mixturewas washed with brine, dried over magnesium sulfate, filtered, andconcentrated under reduced pressure. The residue was subjected to acolumn chromatography on a silica gel (hexane/ethyl acetate, 50:1followed by 10:1) to obtain the mixture (15.6 g) containing3-(bromoethyl)-α,α-dimethylbenzeneacetic acid ethyl ester as an oil.

[1285] This was dissolved in acetic acid (35 mL) and water (35 mL).Hexamethylenetetramine (15.7 g, 112 mmol) was added to the mixture andthe mixture was heated under reflux at 90° C. for 1 hour. Ethyl acetatewas poured into the reaction mixture, and the mixture was washed withwater, a saturated aqueous solution of sodium hydrogen carbonate andbrine, dried over magnesium sulfate, filtered, and concentrated underreduced pressure. The residue was subjected to a column chromatographyon a silica gel (hexane/ethyl acetate, 50:1 followed by 30:1) to obtainthe title compound (5.84 g, yield: 47%).

[1286] An oil.

[1287]¹H NMR (CDCl₃) δ1.91 (3H, t, J=7.1 Hz), 1.63 (6H, s), 4.14 (2H, q,J=7.1 Hz), 7.46-7.65 (2H, m), 7.74-7.89 (2H, m), 10.02 (1H, s).

Reference Example 22

[1288] 3-Cyano-α,α-dimethylbenzeneacetic acid ethyl ester

[1289] 3-Formyl-α,α-dimethylbenzeneacetic acid ethyl ester (5.49 g, 24.9mmol) was dissolved in ethanol (30 mL). Hydroxylamine hydrochloride(3.46 g, 49.9 mmol) and sodium acetate (4.09 g, 49.9 mmol) were added tothe mixture and the mixture was heated under reflux for 40 hours.Ethanol was distilled off under reduced pressure, ethyl acetate waspoured into the residue, and the mixture was washed with water andbrine, dried over sodium sulfate, filtered, and concentrated underreduced pressure. The residue was dissolved in acetic anhydride (30 mL),and stirred at 130° C. for 15 hours. 5 M aqueous solution of sodiumhydroxide was poured into the reaction mixture, and the mixture wasextracted with ethyl acetate. The organic layer was washed with asaturated aqueous solution of sodium hydrogen carbonate, water, andbrine, dried over magnesium sulfate, filtered, and concentrated underreduced pressure. The residue was subjected to a column chromatographyon a silica gel (hexane/ethyl acetate, 40:1 followed by 20:1) to obtainthe title compound (4.21 g, yield: 78%).

[1290] An oil.

[1291]¹H NMR (CDCl₃) δ1.19 (3H, t, J=7.1 Hz), 1.59 (6H, s), 4.13 (2H, q,J=7.1 Hz), 7.39-7.65 (4H, m).

Reference Example 23

[1292] 4-Hydroxy-3-(2-methyl-2-propenyl)benzaldehyde

[1293] The title compound was obtained from p-hydroxybenzaldehyde by themethod similar to that in Reference Example 1. Yield: 59%.

[1294] An oil.

[1295]¹H NMR (CDCl₃) δ1.75 (3H, s), 3.45 (2H, s), 4.89 (1H, s), 4.98(1H, s), 6.19 (1H, br s), 6.96 (1H, d, J=8.1 Hz), 7.70 (1H, d, J=8.1Hz), 7.74 (1H, s), 9.86 (1H, s).

Reference Example 24

[1296] 2,3-Dihydro-2,2-dimethyl-5-benzofurancarboxaldehyde

[1297] To a solution of 4-hydroxy-3-(2-methyl-2-propenyl)benzaldehyde(8.52 g, 4.84 mmol) in toluene (40 mL), boron trifluoride diethyl ethercomplex (6.74 mL, 53.2 mmol) was added, and the mixture was stirred at110° C. for 1 hour. The reaction mixture was washed with water, asaturated aqueous solution of sodium hydrogen carbonate, and brine,dried over magnesium sulfate, filtered, and concentrated under reducedpressure. The residue was subjected to a column chromatography on asilica gel (hexane/ethylacetate, 20:1 followed by 10:1) to obtain thetitle compound (6.41 g, yield: 75%).

[1298] An oil.

[1299]¹H NMR (CDCl₃) δ1.51 (6H, s), 3.06 (2H, s), 6.82 (1H, d, J=8.4Hz), 7.64-7.71 (2H, m), 9.82 (1H, s).

Reference Example 25

[1300] 7-Bromo-2,3-dihydro-2,2-dimethyl-5-benzofurancarboxaldehyde

[1301] To a solution of2,3-dihydro-2,2-dimethyl-5-benzofurancarboxaldehyde (5.90 g, 33.5 mmol)in acetic acid (20 mL), a solution of bromine (2.07 mL, 40.2 mmol) inacetic acid (5 mL) was added, and the mixture was stirred at roomtemperature for 5 hours. An aqueous solution of sodium thiosulfate waspoured into the reaction mixture, and the mixture was extracted twicewith ethyl acetate. The combined organic layer was washed with brine,dried over magnesium sulfate, filtered, and concentrated under reducedpressure. The residue was subjected to a column chromatography on asilica gel (hexane/ethyl acetate, 10:1) to obtain the title compound(8.08 g, yield: 94%).

[1302] An oil.

[1303]¹H NMR (CDCl₃) δ1.57 (6H, s), 3.16 (2H, s), 7.63 (1H, d, J=1.6Hz), 7.83 (1H, d, J=1.8 Hz), 9.77 (1H, s).

Reference Example 26

[1304]7-Bromo-2,3-dihydro-2,2-dimethyl-5-(2-methyl-1-propenyl)benzofuran

[1305] The title compound was obtained from5-bromo-2,3-dihydro-2,2-dimethyl-5-benzofurancarboxaldehyde by themethod similar to that in Reference Example 5. Yield: 81%.

[1306]¹H NMR (CDCl₃) δ1.52 (6H, s), 1.83 (3H, d, J=1.1 Hz), 1.86 (3H, d,J=1.1 Hz), 3.07 (2H, s), 6.12 (1H, s), 6.91 (1H, s), 7.13 (1H, s).

Reference Example 27

[1307]7-Ethylthio-2,3-dihydro-2,2-dimethyl-5-(2-methyl-1-propenyl)benzofuran

[1308] To a solution of 1.54 M solution of tert-butyllithium/pentane(3.45 mL, 5.34 mmol) in tetrahydrofuran (1 mL), a solution ofN,N,N′,N′-tetramethylethylenediamine (0.81 mL, 5.34 mmol) and7-bromo-2,3-dihydro-2,2-dimethyl-5-(2-methyl-1-propenyl)benzofuran (300mg, 1.07 mmol) in tetrahydrofuran (1 mL) was added, and the mixture wasstirred at −78° C. for 30 minutes. A solution of diethyl disulfide (1.32mL, 10.7 mmol) in tetrahydrofuran was added to the mixture and themixture was warmed gradually from −78° C. to room temperature, and thenstirred for 15 hours. Water was poured into the reaction mixture, andthe mixture was extracted twice with ethyl acetate. The combined organiclayer was washed with brine, dried over magnesium sulfate, filtered, andconcentrated under reduced pressure. The residue was subjected to acolumn chromatography on a silica gel (hexane followed by hexane/ethylacetate, 50:1) to obtain the title compound (264 mg, yield: 94%).

[1309] An oil.

[1310]¹H NMR (CDCl₃) δ1.26 (3H, t, J=7.3 Hz), 1.50 (6H, s), 1.84 (3H,s), 1.87 (3H, s), 2.90 (2H, q, J=7.3 Hz), 6.15 (1H, s), 6.89 (1H, s),7.00 (1H, s).

Reference Example 28

[1311] 2,3-Dihydro-2,2,7-trimethylbenzofuran

[1312] To a solution of o-cresol (19.1 mL, 184 mol) inN,N-dimethylformamide (100 mL), 3-chloro-2-methyl-1-propene (20.1 mL,203 mmol) and potassium carbonate (30.5 g, 221 mmol) were added, and themixture was stirred at 80° C. for 3 hours. Ice water was poured into thereaction mixture, and the mixture was extracted twice with ethylacetate. The combined organic layer was washed with water (twice) andbrine, dried over magnesium sulfate, filtered, and concentrated underreduced pressure to obtain 1-methyl-2-[(2-methyl-2-propenyl)oxy]benzene(30.8 g) as an oil.

[1313] This was dissolved in N,N-diethylaniline (27 mL), and stirred at210° C. for 5 hours under nitrogen atmosphere. Ethyl acetate was pouredinto the reaction mixture, and the mixture was washed with 1 Mhydrochloric acid, 2 M hydrochloric acid and brine, dried over magnesiumsulfate, filtered, and concentrated under reduced pressure to obtain2-methyl-6-(2-methyl-2-propenyl)phenol (34.3 g) as an oil.

[1314] 1.20 g of this material was dissolved in ethanol (6 mL). conc.Hydrochloric acid (1.5 mL) was added to the mixture and the mixture washeated under reflux for 2 hours. Ethanol was distilled off under reducedpressure, ethyl acetate was poured into the residue, and the mixture waswashed with water and brine, dried over magnesium sulfate, filtered, andconcentrated under reduced pressure. The residue was subjected to acolumn chromatography on a silica gel (hexane) to obtain the titlecompound (710 mg, yield: 59%).

[1315] An oil.

[1316]¹H NMR (CDCl₃) δ1.47 (6H, s), 2.19 (3H, s), 3.00 (2H, s),6.69-6.76 (1H, m), 6.91-6.98 (2H, m).

Reference Example 29

[1317] 2,3-Dihydro-2,2,7-trimethyl-5-benzofurancarboxaldehyde

[1318] To a solution of phosphorus oxychloride (0.78 mL, 8.38 mmol) inN,N-dimethylformamide (0.71 mL, 9.22 mmol), a solution of2,3-dihydro-2,2,7-trimethylbenzofuran (680 mg, 4.19 mmol) inN,N-dimethylformamide (2 mL) was added, and the mixture was stirred at80° C. for 15 hours. Ice water was poured into the reaction mixture, andthe mixture was neutralized with 5 M aqueous solution of sodiumhydroxide, and extracted twice with ethyl acetate. The combined organiclayer was washed with water (twice) and brine, dried over magnesiumsulfate, filtered, and concentrated under reduced pressure. The residuewas subjected to a column chromatography on a silica gel (hexane/ethylacetate, 30:1 followed by 10:1) to obtain the title compound (640 mg,yield: 80%).

[1319] An oil.

[1320]¹H NMR (CDCl₃) δ1.51 (6H, s), 2.23 (3H, s), 3.05 (2H, s), 7.50(1H, d, J=0.8 Hz), 7.53 (1H, d, J=0.8 Hz), 9.78 (1H, s).

Reference Example 30

[1321] 2,3-Dihydro-2,2,7-trimethyl-5-(2-methyl-1-propenyl)benzofuran

[1322] The title compound was obtained from2,3-dihydro-2,2,7-trimethyl-5-benzofurancarboxaldehyde by the methodsimilar to that in Reference Example 5. Yield: 93%.

[1323] An oil.

[1324]¹H NMR (CDCl₃) δ1.47 (6H, s), 1.85 (6H, s), 2.17 (3H, s), 2.99(2H, s), 6.16 (1H, s), 6.80 (1H, s), 6.85 (1H, s).

Reference Example 31

[1325] 4-Cyclohexylbenzaldehyde

[1326] To a mixture of phenylcyclohexane (24.9 g, 155 mmol) and aluminumchloride (20.9 g, 157 mmol) in nitromethane (200 mL), a solution ofdichloromethylmethyl ether (18.0 g, 157 mmol) in nitromethane (50 mL)was added dropwise at 0° C. over 40 minutes, and the mixture was stirredat 0° C. for 40 minutes. The reaction mixture was poured into ice water,and the organic material was extracted with diethyl ether. The extractwas washed with brine, dried over magnesium sulfate, and then thesolvent was distilled off under reduced pressure to obtain the mixture(27.8 g) containing the title compound. This was used in the nextreaction without further purification.

[1327] An oil.

Reference Example 32

[1328] 4-Cyclohexylbenzonitrile

[1329] A solution of 4-cyclohaxylbenzaldehyde (13.4 g, 71.1 mmol) andhydroxylamine hydrochloride (6.82 g, 98.1 mmol) in formic acid (200 mL)was heated under reflux for 2 hours. The reaction solution was cooled toroom temperature, and then poured into ice water, and the solution wasbasified with potassium hydroxide. The organic material was extractedwith hexane. The extract was washed with brine, dried over sodiumsulfate, and then the solvent was distilled off under reduced pressure.The resultant residue was purified by a column chromatography on asilica gel (hexane/ethyl acetate, 20:1 followed by 10:1) to obtain thetitle compound (5.75 g, yield: 44%).

[1330] An oil.

[1331]¹H NMR (CDCl₃) δ1.26-1.52 (4H, m), 1.74-1.89 (6H, m), 2.56 (1H,br), 7.27-7.39 (2H, m), 7.50-7.62. (2H, m).

Reference Example 33

[1332] 4-Phenoxybenzaldehyde

[1333] A suspension of 4-fluorobenzaldehyde (30.5 g, 246 mmol), phenol(23.5 g, 249 mmol), and potassium carbonate (34.8 g, 252 mmol) inN,N-dimethylformamide (500 mL) was heated under reflux for 11.5 hours.The reaction solution was cooled to room temperature, and then thesolvent was distilled off under reduced pressure. The resultant residuewas combined with water, and the organic material was extracted withethyl acetate. The extract was washed with brine, dried over magnesiumsulfate, and then the solvent was distilled off under reduced pressureto obtain the mixture (48.1 g) containing the title compound. This wasused in the next reaction without further purification.

[1334] An oil.

Reference Example 34

[1335] 4-Phenoxybenzonitrile

[1336] The title compound was obtained from 4-phenoxybenzaldehyde by themethod similar to that in Reference Example 32. Yield: 80%.

[1337]¹H NMR (CDCl₃) δ6.97-7.19 (4H, m), 7.20-7.28 (1H, m), 7.37-7.46(2H, m), 7.57-7.64 (2H, m).

Reference Example 35

[1338] 4-(1-Piperidinyl)benzonitrile

[1339] A suspension of 4-fluorobenzonitrile (6.0 g, 50 mmol), piperidine(4.0 g, 47 mmol), and potassium carbonate (8.5 g, 62 mmol) inN,N-dimethylformamide (100 mL) was stirred at 95° C. for 37 hours. Thereaction solution was cooled to room temperature, and the solvent wasdistilled off under reduced pressure. The resultant residue was combinedwith water, and the organic material was extracted with ethyl acetate.The extract was washed with brine, dried over magnesium sulfate, andthen the solvent was distilled off under reduced pressure. The resultantresidue was purified by a column chromatography on a silica gel(hexane/ethyl acetate, 20:1 followed by 5:1) to obtain the titlecompound (8.3 g, yield: 90%).

[1340]¹H NMR (CDCl₃) δ1.66 (6H, s), 3.33 (4H, s), 6.84 (2H, d, J=8.8Hz), 7.46 (2H, d, J=8.8 Hz).

Reference Example 36

[1341] 3,5-Bis(1,1-dimethylethyl)-4-hydroxybenzonitrile

[1342] The title compound was obtained from3,5-bis(1,1-dimethylethyl)-4-hydroxybenzaldehyde by the method similarto that in Reference Example 32. Yield: 45%.

[1343]¹H NMR (CDCl₃) δ1.44 (18H, s), 5.74 (1H, s), 7.47 (2H, s).

Reference Example 37

[1344] 4-Methyl-2-phenyl-1H-imidazole-5-carbonitrile

[1345] The title compound was obtained from4-methyl-2-phenyl-1H-imidazole-5-carboxaldehyde by the method similar tothat in Reference Example 32. Yield: 54%.

[1346]¹H NMR (DMSO-d₆) δ2.41 (3H, s), 3.19 (1H, s), 7.42-7.54 (3H, m),7.92 (2H, dd, J=7.8, 1.4 Hz).

Reference Example 38

[1347] 4-(1-Methylethoxy)benzonitrile

[1348] A solution of 2-propanol (4.4 g, 73 mmol) and sodium hydride (60%in oil, 2.9 g, 73 mmol) in N,N-dimethylformamide (100 mL) was stirred at0° C. for 10 minutes. A solution of 4-fluorobenzonitrile (7.1 g, 59mmol) in N,N-dimethylformamide (25 mL) was added to the reaction mixtureat 0° C., and stirred at the same temperature for 3 hours, and at roomtemperature further for 15.5 hours. The reaction solution was pouredinto water, and extracted with ethyl acetate. The extract was washedwith brine, dried over magnesium sulfate, and then the solvent wasdistilled off under reduced pressure. The resultant residue wascrystallized from hexane to obtain the title compound (7.4 g, yield:85%).

[1349]¹H NMR (CDCl₃) δ1.36 (6H, d, J=6.2 Hz), 4.52-4.64 (1H, m), 6.91(2H, d, J=8.6 Hz), 7.57 (2H, d, J=8.6 Hz).

Reference Example 39

[1350] 4-Cyanobenzyl acetate

[1351] A mixture of 4-cyanobenzylbromide (12.6 g, 64 mmol) and sodiumacetate (10.6 g, 129 mmol) in N,N-dimethylformamide (50 mL) was stirredat 80° C. for 25 hours. The solvent was distilled off under reducedpressure, the resultant residue was combined with water, and the organicmaterial was extracted with ethyl acetate. The extract was washed withbrine, dried over magnesium sulfate, and then the solvent was distilledoff under reduced pressure. The resultant residue was purified by acolumn chromatography on a silica gel (hexane/ethyl acetate, 20:1followed by 2:1) to obtain the title compound (8.9 g, yield; 80%).

[1352]¹H NMR (CDCl₃) δ2.14 (3H, s), 5.16 (2H, s), 7.47 (2H, d, J=8.4Hz), 7.68 (2H, d, J=8.4 Hz).

Reference Example 40

[1353] 4-[2-(4-Methoxyphenyl)ethoxy]benzonitrile

[1354] The title compound was obtained from 4-methoxyphenethyl alcoholand 4-fluorobenzonitrile by the method similar to that in ReferenceExample 38. Yield 93%.

[1355]¹H NMR (CDCl₃) δ3.06 (2H, t, J=7.0 Hz), 3.80 (3H, s), 4.17 (2H, t,J=7.0 Hz), 6.87 (2H, t, J=8.7 Hz), 6.93 (2H, d, J=9.0 Hz), 7.19 (2H, d,J=8.7 Hz), 7.57 (2H, d, J=9.0 Hz).

Reference Example 41

[1356] 2,3-Dihydro-7-methoxy-5-benzofurancarbonitrile

[1357] The title compound was obtained from7-methoxy-2,3-dihydro-5-benzofurancarboxaldehyde by the method similarto that in Reference Example 32. Yield 77%.

[1358]¹H NMR (CDCl₃) δ3.28 (2H, t, J=8.8 Hz), 3.89 (3H, s), 4.73 (2H, t,J=8.8 Hz), 7.00 (1H, s), 7.16 (1H, s).

Reference Example 42

[1359] 4-[(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)methyl]benzonitrile

[1360] A mixture of 4-cyanobenzylbromide (4.0 g, 20 mmol) and potassiumphthalimide (3.8 g, 21 mmol) in N,N-dimethylformamide (40 mL) wasstirred at room temperature for 20 hours. The reaction solution wasconcentrated under reduced pressure, the resultant residue was combinedwith water, and the organic material was extracted with ethyl acetate.The extract was washed with brine, dried over magnesium sulfate, andthen the solvent was distilled off under reduced pressure to obtain themixture (4.6 g) containing the title compound. This was used in the nextreaction without further purification.

Reference Example 43

[1361] 4-(Aminomethyl)benzonitrile

[1362] A solution of4-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)methyl]benzonitrile (4.6 g,18 mmol) and hydrazine monohydrate (8.9 g, 180 mmol) in ethanol (90 mL)was heated under reflux for 33 hours. The reaction solution was cooledto room temperature, and concentrated under reduced pressure. Theresidue was combined with water, basified with potassium hydroxide, andthen extracted with diethyl ether. The extract was washed with brine,dried over magnesium sulfate, and then the solvent was distilled offunder reduced pressure to obtain the title compound (1.9 g, yield: 81%).

[1363] An oil.

[1364]¹H NMR (CDCl₃) δ3.96 (2H, s), 7.45 (2H, d, J=8.0 Hz), 7.63 (2H, d,J=8.0 Hz).

Reference Example 44

[1365] N-[(4-cyanophenyl)methyl]methanesulfonamide

[1366] To a solution of 4-(aminomethyl)benzonitrile (1.9 g, 14 mol) andtriethylamine (3.0 mL, 22 mmol) in tetrahydrofuran (30 mL),methanesulfonyl chloride (1.1 mL, 14 mmol) was added dropwise at 0° C.The reaction solution was stirred at room temperature for 9 hours. Thereaction solution was poured into water, and the organic material wasextracted with ethyl acetate. The extract was washed with brine, driedover magnesium sulfate, and then the solvent was distilled under reducedpressure to obtain crude crystals. The resultant crude crystals werewashed with hexane-diethylether to obtain the title compound (2.0 g,yield: 66%).

[1367]¹H NMR (CDCl₃) δ2.94 (3H, s), 4.40 (2H, d, J=6.6 Hz), 5.01 (1H,br), 7.50 (2H, d, J=8.6 Hz), 7.67 (2H, d, J=8.6 Hz).

Reference Example 45

[1368] 6-Methoxy-3-pyridinecarbonitrile

[1369] A solution of sodium methoxide (2.42 g, 44.8 mmol) and6-chloronicotinonitrile (3.04 g, 21.9 mmol) in N,N-dimethylformamide (50mL) was stirred at room temperature for 10 hours. The reaction solutionwas poured into water, and the organic material was extracted with ethylacetate. The extract was washed with brine, dried over magnesiumsulfate, and then the solvent was distilled off under reduced pressure.The resultant residue was purified by a column chromatography on asilica gel (hexane/ethyl acetate, 2:1) to obtain the title compound(2.28 g, yield: 78%).

[1370]¹H NMR (CDCl₃) δ4.00 (3H, s), 6.83 (1H, dd, J=8.8, 0.8 Hz), 7.78(1H, dd, J=8.6, 2.4 Hz), 8.50 (1H, d, J=1.4 Hz).

Reference Example 46

[1371] 3-(1-Methylethoxy)benzonitrile

[1372] The title compound was objected from 2-propanol and3-fluorobenzonitrile by the method similar to that in Reference Example38. Yield: 78%.

[1373]¹H NMR (CDCl₃) δ1.35 (6H, d, J=6.0 Hz), 4.51-4.63 (1H, m),7.07-7.13 (2H, m), 7.21 (1H, dt, J=7.6, 1.2 Hz), 7.36 (1H, td, J=7.6,1.4 Hz).

Reference Example 47

[1374] 4-Pyridinecarboxamide 1-oxide

[1375] A solution of isonicotinamide (52 g, 430 mmol) and a 30% aqueoussolution of hydrogen peroxide (65 mL, 570 mol) in acetic acid (170 mL)was stirred at 80° C. for 12 hours. The reaction solution was cooled toroom temperature, precipitated crystals were recovered by filtration,and washed with water and hexane to obtain the title compound (30 g,yield: 50%).

[1376]¹H NMR (DMSO-d₆) δ7.66 (1H, br), 7.82-7.87 (2H, m), 8.17 (1H, br),8.26-8.33 (2H, m).

Reference Example 48

[1377] 4-Methylquinoline 1-oxide

[1378] The title compound was obtained from 4-methylquinoline by themethod similar to that in Reference Example 47. Yield: 75%.

[1379]¹H NMR (CDCl₃) δ2.67 (3H, s), 7.14 (1H, d, J=6.2 Hz), 7.65-7.84(2H, m), 7.96-8.01 (1H, m), 8.45 (1H, d, J=6.4 Hz), 8.79-8.84 (1H, m).

Reference Example 49

[1380] 3-Methylquinoline 1-oxide

[1381] The title compound was obtained from 3-methylquinoline by themethod similar to that in Reference Example 47. Yield: 91%.

[1382]¹H NMR (CDCl₃) δ2.46 (3H, s), 7.53-7.81 (4H, m), 8.43 (1H, s),8.69 (1H, d, J=8.8 Hz).

Reference Example 50

[1383] 7-Methylquinoline 1-oxide

[1384] The title compound was obtained from 7-methylquinoline by themethod similar to that in Reference Example 47. Yield: 46%.

[1385]¹H NMR (CDCl₃) δ2.61 (3H, s), 7.20-7.27 (1H, m), 7.46-7.51 (1H,m), 7.69-7.79 (2H, m), 8.50-8.56 (2H, m).

Reference Example 51

[1386] 4-Pyridinecarboxylic acid ethyl ester 1-oxide

[1387] The title compound was obtained from isonicotinic acid ethylester by the method similar to that in Reference Example 47. Yield: 80%.

[1388]¹H NMR (CDCl₃) δ1.39 (3H, t, J=7.0 Hz), 4.42 (2H, q, J=7.0 Hz),7.92-7.97 (2H, m), 8.33-8.39 (2H, m).

Reference Example 52

[1389] 6-Methylquinoline 1-oxide

[1390] The title compound was obtained from 6-methylquinoline by themethod similar to that in Reference Example 47. Yield: 87%.

[1391]¹H NMR (CDCl₃) δ2.55 (3H, s), 7.22-7.29 (1H, m), 7.56-7.68 (3H,m), 8.47 (1H, d, J=6.0 Hz) 8.64 (1H, d, J=8.8 Hz).

Reference Example 53

[1392] 7-Methoxy-2-benzofurancarboxylic acid

[1393] A solution of o-vanillin (51 g, 340 mmol), bromomalonic aciddiethyl ester (73 g, 310 mmol), and potassium carbonate (82 g, 590 mmol)in 2-butanone (200 mL) was heated under reflux for 3.5 hours. Thereaction solution was cooled to room temperature, and then the solventwas distilled off under reduced pressure. The resultant residue wascombined with water, and the organic material was extracted with diethylether. The extract was washed with brine, dried over magnesium sulfate,and then the solvent was distilled off under reduced pressure. Thesolution of the resultant residue and potassium hydroxide (43 g, 740mmol) in ethanol (400 mL) was heated under reflux for 1 hour. Thereaction solution was cooled to room temperature, poured into water, andthen. acidified by the addition of 6 M hydrochloric acid. The organicmaterial was extracted with ethyl acetate, the extract was washed withbrine, dried over magnesium sulfate, and then the solvent was distilledoff under reduced pressure. The resultant residue was crystallized fromdiisopropyl ether to obtain the title compound (26 g, yield: 45%).

[1394]¹NMR (DMSO-d₆) δ3.97 (3H, s), 5.71 (1H, s), 7.09 (1H, dd, J=7.4,1.5 Hz), 7.27 (1H, t, J=7.8 Hz), 7.33 (1H, dd, J=7.8, 1.5 Hz), 7.65 (1H,s).

Reference Example 54

[1395] 7-Methoxybenzofuran

[1396] A suspension of 7-methoxy-2-benzofurancarboxylic acid (23 g, 120mmol) and copper (powder, 5.8 g, 92 mmol) in quinoline (70 mL) washeated under reflux for 12 hours. The reaction solution was cooled toroom temperature. The insolubles were filtered off, filtrate was pouredinto water, and acidified by the addition of 2 M hydrochloric acid. Theorganic material was extracted with ethyl acetate, the extract waswashed with brine, dried over magnesium sulfate, and then the solventwas distilled off under reduced pressure. The resultant residue waspurified by a column chromatography on a silica gel (hexane/ethylacetate, 10:1) to obtain the title compound (8.0 g, yield 46%).

[1397]¹H NMR (CDCl₃) δ4.02 (3H, s), 6.77 (1H, d, J=2.2 Hz), 6.81 (1H,dd, J=6.8, 2.2 Hz), 7.12-7.22 (2H, m), 7.63 (1H, d, J=2.2 Hz).

Reference Example 55

[1398] 2,3-Dihydro-7-methoxybenzofuran

[1399] To a solution of 7-methoxybenzofuran (8.0 g, 54 mmol) in aceticacid (55 mL), 10% palladium on carbon (3.9 g, 49% hydrate) was added,and the mixture was stirred at room temperature for 8 hours underhydrogen atmosphere. The reaction solution was filtered to remove thecatalyst, and then the filtrate was concentrated under reduced pressure.The resultant residue was neutralized by the addition of 8 M aqueoussolution of sodium hydroxide, and the organic material was extractedwith diethyl ether. The extract was washed with brine, dried overmagnesium sulfate, and then the solvent was distilled off under reducedpressure to obtain the title compound (7.2 g, yield: 90%).

[1400] An oil.

[1401]¹H NMR (CDCl₃) δ3.17 (2H, t, J=8.6 Hz), 3.82 (3H, s), 4.56 (2H, t,J=8.6 Hz), 6.65-6.72 (1H, m), 6.72-6.78 (2H, m).

Reference Example 56

[1402] 2,3-Dihydro-7-methoxy-5-benzofurancarboxaldehyde

[1403] To N,N-dimethylformamide (8.0 mL), phosphorus oxychloride (8.0mL, 86 mmol) was added dropwise at 0° C. A solution of2,3-dihydro-7-methoxybenzofuran (6.7 g, 44 mmol) inN,N-dimethylformamide (26 mL) was added to the reaction mixture and themixture was stirred at 80° C. for 1 hour. The reaction solution wascooled to room temperature, and then poured into water. The solution wasbasified by the addition of 8 M aqueous solution of sodium hydroxide,and then extracted with diethyl ether. The extract was washed withbrine, dried over magnesium sulfate, and then the solvent was distilledoff under reduced pressure. The resultant residue was purified by acolumn chromatography on a silica gel (hexane/ethyl acetate, 10:1followed by 5:2) to obtain the title compound (3.5 g, yield: 44%).

[1404]¹H NMR (CDCl₃) δ3.32 (2H, t, J=8.8 Hz), 3.94 (3H, s), 4.77 (2H, t,J=8.8 Hz), 7.32 (1H, d, J=1.2 Hz), 7.38 (1H, d, J=1.2 Hz), 9.82 (1H, s).

Reference Example 57

[1405] 2,3-Dihydro-7-methoxy-5-(2-methyl-1-propenyl)benzofuran

[1406] To a suspension of2,3-dihydro-7-methoxy-5-benzofurancarboxaldehyde (3.5 g, 20 mmol) andisopropyltriphenylphosphonium iodide (10 g, 24 mmol) in tetrahydrofuran(60 mL), sodium hydride (60% in oil, 1.1 g, 28 mmol) was added at 0° C.,and the mixture was heated under reflux for 2.5 hours. The reactionsolution was cooled to room temperature, and poured into water. Theorganic material was extracted with ethyl acetate, the extract waswashed with brine, dried over magnesium sulfate, and then the solventwas distilled off under reduced pressure. The resultant residue waspurified by a column chromatography on a silica gel (hexane/ethylacetate, 50:1 followed by 10:1) to obtain the title compound (2.0 g,yield: 50%).

[1407] An oil.

[1408]¹H NMR (CDCl₃) δ1.86-1.88 (6H, m), 3.22 (2H, t, J=8.6 Hz), 3.86(3H, s), 4.62 (2H, t, J=8.6 Hz), 6.20 (1H, br s), 6.61 (1H, s), 6.71(1H, s).

Reference Example 58

[1409] 3-Iodo-5-methoxy-4-[(2-methyl-2-propenyl)oxy]benzaldehyde

[1410] A suspension of 5-iodovanillin (20 g, 72 mmol),3-chloro-2-methyl-1-propene (13 g, 140 mmol), and potassium carbonate(20 g, 140 mmol) in N,N-dimethylformamide (100 mL) was stirred at 80° C.for 6 hours. The reaction solution was cooled to room temperature, andthen the solvent was distilled off under reduced pressure. The residuewas combined with water, and the organic material was extracted withethyl acetate. The extract was washed with brine, dried over magnesiumsulfate, and then the solvent was distilled off under reduced pressure.The resultant residue was purified by a column chromatography on asilica gel (hexane/ethyl acetate, 10:1 followed by 5:1) to obtain thetitle compound (22 g, yield: 93%).

[1411] An oil.

[1412]¹H NMR (CDCl₃) δ1.94 (3H, s), 3.91 (3H, s), 4.54 (2H, s), 5.01(1H, s), 5.17 (1H, s), 7.41 (1H, d, J=1.8 Hz), 7.87 (1H, d, J=1.8 Hz),9.83 (1H, s).

Reference Example 59

[1413] 2,3-Dihydro-7-methoxy-3,3-dimethyl-5-benzofurancarboxaldehyde

[1414] A suspension of3-iodo-5-methoxy-4-[(2-methyl-2-propenyl)oxy]benzaldehyde (22 g, 66mmol), palladium(II) acetate (0.60 g, 27 mmol), potassium carbonate (9.0g, 65 mmol), sodium formate (4.3 g, 63 mmol), and tetrabutylammoniumbromide (18 g, 55 mol) in N,N-dimethylformamide (300 mL) was stirred at100° C. for 2.5 hours. The reaction solution was cooled to roomtemperature, and then the solvent was distilled off under reducedpressure. The residue was combined with water, and the organic materialwas extracted with ethyl acetate. The extract was washed with brine,dried over magnesium sulfate, and then the solvent was distilled offunder reduced pressure. The resultant residue was purified by a columnchromatography on a silica gel (hexane/ethyl acetate, 10:1 followed by2:1) to obtain the title compound (7.7 g, yield: 57%).

[1415] An oil.

[1416]¹H NMR (CDCl₃) δ1.40 (6H, s), 3.95 (3H, s), 4.43 (2H, s),7.31-7.32 (2H, m), 9.84 (1H, s).

Reference Example 60

[1417]2,3-Dihydro-7-methoxy-3,3-dimethyl-5-(2-methyl-1-propenyl)benzofuran

[1418] The title compound was obtained from2,3-dihydro-7-methoxy-3,3-dimethyl-5-benzofurancarboxaldehyde andisopropyltriphenylphosphonium iodide by the method similar to that inReference Example 57. Yield 59%.

[1419] An oil.

[1420]¹H NMR (CDCl₃) δ1.33 (6H, s), 1.87-1.89 (6H, m), 3.87 (3H, s),4.29 (2H, s), 6.23 (1H, br s), 6.61 (1H, s), 6.62 (1H, s).

Reference Example 61

[1421] 2,3-Dihydro-7-methoxy-2,2-dimethyl-5-benzofuranmethanol

[1422] A solution of2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofurancarboxaldehyde (7.5 g, 36mmol) and sodium borohydride (0.72 g, 19 mmol) in methanol (60 mL) wasstirred at 0° C. for 3 hours. The reaction solution was concentratedunder reduced pressure, and the resultant residue was combined withwater. The solution was acidified by the addition of 1 M hydrochloricacid, and then the organic material was extracted with ethyl acetate.The extract was washed with brine, dried over magnesium sulfate, andthen the solvent was distilled off under reduced pressure. The resultantresidue was purified by a column chromatography on a silica gel(hexane/ethyl acetate, 5:1 followed by 2:1) to obtain the title compound(5.8 g, yield:77%).

[1423] An oil.

[1424]¹H NMR (CDCl₃) δ1.50 (6H, s), 2.20 (1H, br), 3.01 (2H, s), 3.86(3H, s), 4.57 (2H, s), 6.76 (2H, s).

Reference Example 62

[1425][(2,3-Dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)methyl]triphenylphosphoniumbromide

[1426] To a solution of2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranmethanol (5.8 g, 28 mmol)in diethyl ether (90 mL), phosphorus tribromide (0.90 mL, 9.5 mmol) wasadded dropwise at 0° C. The reaction solution was stirred at 0° C. for30 minutes, and then poured into water. The organic layer was washedwith brine, dried over magnesium sulfate, and then the solvent wasdistilled off under reduced pressure. The solution of the resultantresidue (7.2 g) and triphenylphosphine (7.5 g, 29 mmol) in toluene (70mL) was stirred at 80° C. for 10 hours. The reaction solution was cooledto room temperature, and precipitated crystals were recovered byfiltration and washed with diethyl ether to obtain the title compound(12 g, yield: 84%).

[1427]¹H NMR (CDCl₃) δ1.45 (6H, s), 2.83 (2H, s), 3.49 (3H, s), 5.33(2H, d, J=13.6 Hz), 6.50 (1H, s), 6.58 (1H, s), 7.59-7.81 (15H, m).

Reference Example 63

[1428]5-(2-Ethyl-1-butenyl)-2,3-dihydro-7-methoxy-2,2-dimethylbenzofuran

[1429] To a suspension of[(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)methyl]triphenylphosphoniumbromide (5.6 g, 10 mmol) in tetrahydrofuran (50 mL), potassiumtert-butoxide (1.3 g, 11 mmol) was added at 0° C. 3-pentanone (2.2 mL,21 mmol) was added to the reaction mixture and the mixture was heatedunder reflux for 20 hours. The reaction solution-was cooled to roomtemperature, and then poured into water. The solution was acidified bythe addition of 1 M hydrochloric acid, and then the organic material wasextracted with ethyl acetate. The extract was washed with brine, driedover magnesium sulfate, and then the solvent was distilled off underreduced pressure. The resultant residue was purified by a columnchromatography on a silica gel (hexane/ethyl acetate, 50:1 followed by5:1) to obtain the title compound (2.4 g, yield: 87%).

[1430] An oil.

[1431]¹H NMR (CDCl₃) δ1.09 (6H, td, J=7.6, 1.8 Hz), 1.51 (6H, s),2.12-2.34 (4H, m), 3.02 (2H, s), 3.85 (3H, s), 6.16 (1H, s), 6.61 (1H,s), 6.64 (1H, s).

Reference Example 64

[1432] 2,3-Dihydro-5-benzofurancarbonitrile

[1433] A solution of 2,3-dihydro-5-benzofurancarboxaldehyde (5.00 g,33.7 mmol) and hydroxylamine hydrochloride (3.52 g, 50.6 mmol) in formicacid (70 mL) was heated under reflux for 2 hours. The reactionmixture-was poured into ice water, and neutralized with potassiumhydroxide to recover precipitated crystals. The resultant crystals weredissolved in ethyl acetate, dried over magnesium sulfate, filtered, andconcentrated under reduced pressure. The residue was recrystallized fromethyl acetate-hexane to obtain the title compound (3.03 g, yield: 62%).

[1434] Melting point: 69-70° C.

[1435]¹H NMR (CDCl₃) δ3.26 (2H, d, J=8.8 Hz), 4.67 (2H, d, J=8.8 Hz),6.82 (1H, dd, J=8.8, 1.0 Hz), 7.42-7.46 (2H, m).

Reference Example 65

[1436] 2,3-Dihydro-7-methoxy-2,2-dimethyl-5-benzofurancarbonitrile

[1437] A solution of2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofurancarboxaldehyde (8.40 g,40.7 mmol) and hydroxylamine hydrochloride (4.25 g, 61.1 mmol) in formicacid (100 mL) was heated under reflux for 3 hours. The reaction mixturewas poured into ice water, neutralized with potassium hydroxide torecover precipitated crystals. The resultant crystals were dissolved inethyl acetate, dried over magnesium sulfate, filtered, and concentratedunder reduced pressure. The residue was subjected to a columnchromatography on a silica gel (hexane/ethyl acetate, 5:1) to obtain thetitle compound (6.73 g, yield: 81%).

[1438] Melting point: 73-74° C.

[1439]¹H NMR (CDCl₃) δ1.54 (6H, s), 3.07 (2H, s), 3.89 (3H, s), 7.00(1H, br s), 7.12 (1H, br s).

Reference Example 66

[1440] 4-(Phenylthio)benzonitrile

[1441] To a solution of 4-fluorobenzonitrile (5.00 g, 41.3 mmol) inN,N-dimethylformamide (100 mL), thiophenol (4.55 g, 41.3 mol) andpotassium carbonate (5.71 g, 41.3 mmol) were added, and the mixture wasstirred at 150° C. for 2.5 days under nitrogen atmosphere. The reactionsolution was cooled to room temperature, the reaction solvent wasconcentrated and distilled off under reduced pressure, and the residuewas poured into water. The organic material was extracted with ethylacetate, the extract was washed with brine, dried over magnesiumsulfate, filtered, and concentrated under reduced pressure. The residuewas subjected to a column chromatography on a silica gel (hexanefollowed by hexane/ethyl acetate, 20:1) to obtain the title compound(6.03 g, yield: 69%).

[1442] An oil.

[1443]¹H NMR (CDCl₃) δ7.15-7.20 (2H, m), 7.42-7.55 (7H, m).

Reference Example 67

[1444] 4-(1-Methylethyl)benzonitrile

[1445] The title compound was obtained employing4-(1-methylethyl)benzaldehyde by the method similar to that in ReferenceExample 65. Yield: 77%.

[1446] An oil.

[1447]¹H NMR (CDCl₃) δ1.26 (6H, d, J=7.0 Hz), 2.89-3.03 (1H, m), 7.00(2H, ddd, J=8.4, 2.0, 1.6 Hz), 7.12 (2H, ddd, J=8.4, 2.0, 1.6 Hz).

Reference Example 68

[1448] 5-Methyl-2-thiophene carbonitrile

[1449] The title compound was obtained employing5-methyl-2-thiophenecarboxaldehyde by the method similar to that inReference Example 65. Yield: 60%.

[1450] An oil.

[1451] H NMR (CDCl₃) δ2.46 (3H, s), 6.95 (1H, d, J=5.0 Hz), 7.47 (1H, d,J=5.0 Hz).

Reference Example 69

[1452] 4-(Trifluoromethoxy)benzonitrile

[1453] The title compound was obtained employing4-(trifluoromethoxy)benzaldehyde by the method similar to that inReference Example 65. Yield: 71%.

[1454] An oil.

[1455]¹H NMR (CDCl₃) δ7.33 (2H, d, J=8.6 Hz), 7.76 (2H, d, J=8.6 Hz).

Reference Example 70

[1456] 3,5-Dichloro-4-pyridinecarboxaldehyde

[1457] To a solution of diisopropylamine (24.9 mL, 177 mmol) intetrahydrofuran (150 mL), 1.6 M solution of n-butyllithium/hexane (116mL, 186 mmol) was added dropwise at −78° C. over 20 minutes undernitrogen atmosphere, and then a solution of 3,5-dichloropyridine (25.0g, 169 mmol) in tetrahydrofuran (100 mL) was added dropwise over 15minutes, and the mixture was stirred further for 20 minutes.N,N-dimethylformamide (18.3 mL, 237 mmol) was added to the mixture, andthe mixture was stirred at room temperature for 18 hours. The reactionsolution was poured into a solution of conc. hydrochloric acid (60 mL)in water (400 mL), and stirred at room temperature for 24 hours. Theaqueous layer was separated, and the organic material was extracted withdiethyl ether. The extract was washed with brine, dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas subjected to a column chromatography on a silica gel (hexane/ethylacetate, 10:1 followed by 5:1) to obtain the title compound (7.96 g,yield: 27%).

[1458]¹H NMR CDCl₃) δ8.64 (2H, s), 10.46 (1H, s).

Reference Example 71

[1459] 3,5-Dichloro-4-pyridinecarbonitrile

[1460] The title compound was obtained employing3.5-dichloro-4-pyridinecarboxaldehyde by the method similar to that inReference Example 64. Yield: 86%.

[1461] Melting point: 114-115° C.

[1462]¹H NMR (CDCl₃) δ8.69 (2H, s).

Reference Example 72

[1463] 3-Methyl-2-thiophene carbonitrile

[1464] The title compound was obtained employing3-methyl-2-thiophenecarboxaldehyde by the method similar to that inReference Example 65. Yield: 59%.

[1465]¹H NMR (CDCl₃) δ2.55 (3H, d, J=1.0 Hz), 6.78 (1H, dd, J=4.0, 1.0Hz), 7.44 (1H, d, J=4.0 Hz).

Reference Example 73

[1466] 4-(Methylsulfinyl)benzonitrile

[1467] To a mixture solution of 4-(methylthio)benzonitrile (5.00 g, 33.5mmol) in methanol (200 mL), tetrahydrofuran (50 mL) and water (50 mL),sodium metaperiodate (7.89 g, 36.9 mmol) was added, and the mixture washeated under reflux for 2 hours. The reaction solution was cooled toroom temperature, and then precipitated crystals were recovered byfiltration, washed with water, and air-dried to obtain the titlecompound (4.39 g, yield: 79%).

[1468] Melting point: 87-9020 C.

[1469]¹H NMR (CDCl₃) δ2.81 (3H, s), 7.89 (2H, dd, J=8.4, 2.0 Hz), 8.07(2H, dd, J=8.4, 2.0 Hz).

Reference Example 74

[1470] 4-(Methylsulfonyl)benzonitrile

[1471] To a solution of 4-(methylthio)benzonitrile (5.00 g, 33.5 mmol)in dichloromethane (150 mL), m-chloroperbenzoic acid (15.0 g, 73.7 mmol)was added, and the mixture was stirred at 0° C. for 30 minutes, and atroom temperature further for 5 hours. The reaction solution was pouredinto 2 M aqueous solution of sodium hydroxide, and extracted withdichloromethane. The extract was washed with a mixture aqueous solutionof sodium hydroxide, sodium thiosulfate, and sodium iodide, and brine,dried over magnesium sulfate, filtered, and concentrated under reducedpressure. The residue was recrystallized from ethyl acetate-hexane toobtain the title compound (4.53 g, yield: 75%).

[1472] Melting point: 142-144° C.

[1473]¹H NMR (CDCl₃) δ3.10 (3H, s), 7.90 (2H, d, J=8.8 Hz), 8.10 (2H, d,J=8.8 Hz).

Reference Example 75

[1474] 3,4,5-Trimethoxybenzonitrile

[1475] The title compound was obtained employing3,4,5-trimethoxybenzaldehyde by the method similar to that in ReferenceExample 65. Yield: 60%.

[1476] Melting point: 93-94° C.

[1477]¹H NMR (CDCl₃) δ3.89 (6H, s), 3.91 (3H, s), 6.87 (2H, s).

Reference Example 76

[1478] 2,2′-Bipyridyl 1-oxide

[1479] To a solution of 2,2′-bipyridyl (25.0 g, 160 mmol) in chloroform(400 mL), m-chloroperbenzoic acid (38.4 g, 160 mmol) was added withcooling in ice, and the mixture was stirred at room temperature for 12hours. The reaction solution was washed with a 5% aqueous solution ofsodium carbonate, and the aqueous layer was extracted withdichloromethane. The combined organic layer was washed with brine, driedover magnesium sulfate, filtered and concentrated under reducedpressure. The residue was subjected to a basic column chromatography ona silica gel (hexane/ethyl acetate 1:1 followed by ethyl acetate), andthe precipitated crystals were washed with diethyl ether to obtain thetitle compound (16.1 g, yield: 58%).

[1480] Melting point: 58-6020 C.

[1481]¹H NMR (CDCl₃) δ7.45-7.52 (3H, m), 7.89-7.98 (1H, m), 8.09-8.14(1H, m), 8.35-8.39 (1H, m), 8.73-8.78 (2H, m).

Reference Example 77

[1482] 1-[2,2′-Bipyridin]-6-yl-1,6-dihydro-6-oxo-3-pyridinecarboxamide

[1483] To a solution of 6-chloronicotinamide (4.70 g, 30.0 mmol, and2,2′-bipyridyl-1-oxide (10.3 g, 60.0 mmol) in xylene (90 mL) and aceticacid (18 mL), a 25% solution of hydrogen bromide/acetic acid (12 mL) wasadded, and the mixture was heated under reflux for 10 hours. Thereaction mixture was poured into an aqueous solution of sodiumhydroxide, and precipitated crystals were recovered, and air-dried toobtain the title compound (3.20 g, yield: 36%).

[1484]¹H NMR (CDCl₃) δ6.60 (1H, d, J=10.0 Hz), 7.39-7.66 (3H, m),7.83-8.03 (3H, m), 8.14-8.51 (3H, m), 8.68-8.75 (2H, m).

Reference Example 78

[1485] 1-[2,2′-Bipyridin]-6-yl-1,6-dihydro-6-oxo-3-pyridinecarbonitrile

[1486] To a solution of N,N-dimethylformamide (2.04 mL, 26.4 mmol) inacetonitrile (30 mL), oxalyl chloride (2.09 mL, 24.0 mmol) was addeddropwise with cooling on ice, and the mixture was stirred at the sametemperature for 15 minutes.1-[2,2′-bipyridin]-6-yl-1,6-dihydro-6-oxo-3-pyridinecarboxamide (3.50 g,12.0 mmol) was added to the mixture, triethylamine (7.36 mL. 52.8 mmol)was added dropwise to the mixture with cooling in ice, and then themixture was stirred at room temperature for 24 hours. The reactionsolvent was concentrated and distilled off under reduced pressure, andthe residue was poured into water. The precipitated crystals wererecovered, and dissolved in chloroform. This was dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas washed with diethyl ether to obtain the title compound (2.06 g,yield: 63%).

[1487]¹H NMR (CDCl₃) δ6.69 (1H, d, J=9.6 Hz), 7.51 (1H, ddd, J=7.4, 4.8,1.0 Hz), 7.82 (1H, dd, J=9.6, 2.2 Hz), 7.83 (1H, d, J=7.6 Hz), 7.99 (1H,td, J=7.6, 1.8 Hz), 8.19 (1H, t, J=7.6 Hz), 8.42 (1H, d, J=7.6 Hz), 8.49(1H, d, J=7.6 Hz), 8.74 (1H, dd, J=4.8, 0.6 Hz), 8.97 (1H, d, J=2.2 Hz).

Reference Example 79

[1488]1,6-Dihydro-1-(8-methyl-2-quinolinyl)-6-oxo-3-pyridinecarbonitrile

[1489] To a solution of 6-chloronicotinamide (5.90 g, 37.7 mmol) and8-methylquinoline 1-oxide (9.00 g, 56.5 mmol) in xylene (90 mL) andacetic acid (18 mL), a 25% solution of hydrogen bromide/acetic acid (12mL) was added, and the mixture was heated under reflux for 6 hours. Thereaction mixture was poured into an aqueous solution of sodium hydroxideand a precipitated crystals were recovered, and air-dried to obtain1,6-dihydro-1-(8-methyl-2-quinolinyl)-6-oxo-3-pyridinecarboxamide (9.03g, yield: 86%).

[1490] To a solution of N,N-dimethylformamide (7.48 mL 96.6 mmol) inacetonitrile (200 mL), oxalyl chloride was then added dropwise withcooling in ice, and the mixture was stirred at the same temperature for15 minutes.1,6-dihydro-1-(8-methyl-2-quinolyl)-6-oxo-3-pyridinecarboxamide (9.00 g,32.2 mmol) was added to the mixture, and then triethylamine (26.9 mL,193 mmol) was added dropwise to the mixture with cooling in ice, and themixture was stirred at room temperature for 20 hours. The reactionsolvent was concentrated and distilled off under reduced pressure, andthe residue was poured into an aqueous solution of sodium hydroxide. Theorganic material was extracted with ethyl acetate and chloroform, washedwith brine, dried over sodium sulfate, filtered, and concentrated underreduced pressure. The residue was subjected to a column chromatographyon a basic silica gel (hexane/ethyl acetate, 2:1), and precipitatedcrystals were washed with diethyl ether to obtain the title compound(2.04 g, yield: 25%).

[1491] Melting point 269-271° C.

[1492]¹H NMR (CDCl₃) δ2.73 (3H, s), 6.70 (1H, dd, J=9.6, 0.6 Hz), 7.62(1H, dd, J=7.6, 7.0 Hz), 7.73 (1H, d, J=7.0 Hz), 7.84 (1H, d, J=8.8 Hz),7.84 (1H, dd, J=9.6, 2.6 Hz), 7.93 (1H, d, J=7.6 Hz), 8.55 (1H, d, J=8.8Hz), 8.93 (1H, d, J=2.6 Hz).

Reference Example 80

[1493] 1,6-Dihydro-1-(4-methyl-2-pyridinyl)-6-oxo-3-pyridinecarboxamide

[1494] To a solution of 6-chloronicotinamide (6.68 g, 42.7 mmol) and4-methylpyridine 1-oxide (9.32 g, 85.4 mmol) in xylene (120 mL) andacetic acid (25 mL), a 25% solution of hydrogen bromide/acetic acid (15mL) was added, and the mixture was heated under reflux for 3 hours. Thereaction mixture was poured into an aqueous solution of sodiumhydroxide, and precipitated crystals were recovered by filtration, andair-dried to obtain the title compound (5.14 g, yield: 56%).

[1495]¹H NMR (CDCl₃) δ2.42 (3H, s), 6.55 (1H, d, J=9.4 Hz), 7.33 (1H, brs), 7.36-7.40 (1H, m), 7.61-7.62 (1H, m), 7.86 (1H, br s), 7.96 (1H, dd,J=9.4, 2.6 Hz), 8.49 (1H, d, J=2.6 Hz), 8.51 (1H, s).

Reference Example 81

[1496] 1,6-Dihydro-1-(4-methyl-2-pyridinyl)-6-oxo-3-pyridinecarbonitrile

[1497] To a solution of N,N-dimethylformamide (2.30 mL, 29.7 mmol) inacetonitrile (70 mL), oxalyl chloride (2.36 mL, 27.0 mmol) was addeddropwise with cooling in ice, and the mixture was stirred at the sametemperature for 15 minutes.1,6-dihydro-1-(4-methyl-2-pyridinyl)-6-oxo-3-pyridinecarboxamide (2.88g, 13.5 mmol) was added to the mixture, triethylamine (4.14 mL, 29.7mmol) was added dropwise to the mixture with cooling in ice, and thenthe mixture was stirred at room temperature for 12 hours. The reactionsolvent was concentrated and distilled off under reduced pressure, andthe residue was poured into an aqueous solution of sodium hydroxide. Theorganic material was extracted with ethyl acetate, washed with brine,dried over sodium sulfate, filtered, and concentrated under reducedpressure. The residue was subjected to a column chromatography on abasic silica gel (hexane/ethyl acetate, 2:1 followed by 1:1), andprecipitated crystals were washed with diethyl ether to obtain the titlecompound (2.02 g, yield: 71%).

[1498] Melting point: 166-168° C.

[1499]¹H NMR (CDCl₃) δ2.47 (3H, s), 6.68 (1H, dd, J=9.4, 0.8 Hz),7.20-7.24 (1H, m), 7.45 (1H, dd, J=9.4, 2.6 Hz), 7.71-7.73 (1H, m), 8.43(1H, d, J=5.0 Hz), 8.46 (1H, d, J=0.8 Hz).

Reference Example 82

[1500] 2-Chlorocyclopentanone

[1501] To a solution of cyclopentanone (84.1 g, 1.00 mol) andN-chlorosuccinimide (134 g, 1.00 mol) in carbon tetrachloride (250 mL),2,2′-azobis(isobutyronitrile) (1.64 g, 0.10 mol) was added, and themixture was stirred under a light irradiation for 6 hours. The reactionsolution was filtered, and concentrated under reduced pressure. Theresidue was distilled under reduced pressure to obtain the titlecompound (59.2 g, yield: 50%).

[1502] Boiling point: 80-86° C./1.7 kPa (13 mmHg).

[1503]¹H NMR (CDCl₃) δ1.84-2.72 (6H, m), 4.12 (1H, t, J=6.8 Hz).

Reference Example 83

[1504] 2-(2-Methoxyphenoxy)cyclopentanone

[1505] To a solution of guaiacol (31.0 g, 250 mmol) inN,N-dimethylformamide (400 mL), sodium hydride (60% suspension in oil)(12.0 g, 300 mmol) was added, and the mixture was stirred. at 0° C. for30 minutes. A solution of 2-chlorocyclopentanone (59.2 g, 499 mmol) inN,N-dimethylformamide (100 mL) was added dropwise to the mixture, andthe mixture was stirred at 0° C. further for 1 hour. The reactionsolvent was concentrated and distilled off under reduced pressure, andthe residue was poured into water. The organic material was extractedwith ethyl acetate, the extract was washed with brine, dried overmagnesium sulfate, filtered, and concentrated under reduced pressure.The residue was subjected to a column chromatography on a silica gel(hexane/ethyl acetate, 4:1) to obtain the title compound (28.4 g, yield:55%).

[1506] An oil.

[1507]¹H NMR (CDCl₃) δ1.62-2.51 (6H, m), 3.86 (3H, s), 4.61 (1H, td,J=7.8, 1.4 Hz), 6.84-7.04 (4H, m).

Reference Example 84

[1508] 1-Methoxy-2-[(2-methylenecyclopentyl)oxy]benzene

[1509] To a solution of methyltriphenylphosphonium bromide (103 g, 289mmol) in tetrahydrofuran (600 mL), potassium tert-butoxide (30.9 g, 275mol) was added, and the mixture was stirred at 0° C. for 3 hours. Asolution of 2-(2-methoxyphenoxy)cyclopentanone (28.4 g, 138 mmol) intetrahydrofuran (200 mL) was added dropwise, and the mixture was stirredat 0° C. further for 1 hour. The reaction solution was combined withwater, and the organic layer was separated. The aqueous layer wasextracted with ethyl acetate, and the combined organic layer was washedwith brine, dried over magnesium sulfate, filtered, and concentratedunder reduced pressure. The residue was subjected to a columnchromatography on a silica gel (hexane/ethyl acetate, 20:1) to obtainthe title compound (22.4 g, yield: 79%).

[1510] An oil.

[1511]¹H NMR (CDCl₃) δ1.60-2.55 (6H, m), 3.85 (3H, s), 4.89-4.93 (1H,m), 5.07-5.17 (2H, m), 6.83-7.00 (4H, m).

Reference Example 85

[1512] 2-(1-Cyclopenten-1-ylmethyl)-6-methoxyphenol

[1513] 1-Methoxy-2-[(2-methylenecyclopentyl)oxy]benzene (22.4 g, 110mmol) was dissolved in N,N-diethylaniline (30 mL), and stirred at 180°C. for 3 hours under nitrogen atmosphere. The reaction mixture wascooled with ice, combined with 2 M hydrochloric acid, and extracted withethyl acetate. The organic layer was washed with brine, dried overmagnesium sulfate, filtered, and concentrated under reduced pressure.The residue was subjected to a column chromatography on a silica gel(hexane/ethyl acetate, 50:1) to obtain the title compound (19.3 g,yield: 86%).

[1514] An oil.

[1515]¹H NMR (CDCl₃) δ1.78-1.94 (2H, m), 2.24-2.36 (4H, m), 3.42 (2H,s), 3.88 (3H, s), 5.30-5.32 (1H, m), 5.68 (1H, s), 6.70-6.83 (3H, m).

Reference Example 86

[1516] 7-Methoxyspiro[benzofuran-2 (3H),1′-cyclopentane]

[1517] To a solution of 2-(1-cyclopentan-1-ylmethyl)-6-methoxyphenol(22.4 g, 110 mmol) in methanol (200 mL), conc. sulfuric acid (20 mL) wasadded dropwise with cooling In ice, and the mixture was heated underreflux for 4 hours. The reaction solvent was concentrated and distilledunder reduced pressure, and the residue was poured into ice water. Theorganic material was extracted with ethyl acetate, washed with brine,dried over magnesium sulfate, filtered, and concentrated under reducedpressure. The residue was subjected to a column chromatography on asilica gel (hexane/ethyl acetate, 50:1) to obtain the title compound(17.0 g, 88%).

[1518] An oil.

[1519]¹H NMR (CDCl₃) δ1.67-2.21 (8H, m), 3.19 (2H, s), 3.86 (3H, s),6.70-6.80 (3H, m).

Reference Example 87

[1520] 7-Methoxyspiro[benzofuran-2 (3H),1′-cyclopentane]-5-carboxaldehyde

[1521] Phosphorus oxychloride (15.5 mL, 166 mmol) was added dropwise toN,N-dimethylformamide (6.44 mL, 166 mol), a solution of7-methoxyspiro[benzofuran-2(3H),1-cyclopentane] (17.0 g, 83.2 mmol) inN,N-dimethylformamide (30 mL) was added dropwise with cooling in ice,and then the mixture was stirred at 80° C. for 6 hours. The reactionmixture was poured into ice water, neutralized with 8 M aqueous solutionof sodium hydroxide, and then extracted with ethyl acetate. The extractwas washed with brine, dried over sodium sulfate, filtered, concentratedunder reduced pressure. The residue was subjected to a columnchromatography on a silica gel (hexane/ethyl acetate, 10:1), andcrystallized from diethyl ether-hexane to obtain the title compound(11.0 g, yield: 57%).

[1522] Melting point: 54° C.

[1523]¹H NMR (CDCl₃) δ1.70-2.26 (8H, m), 3.26 (2H, s), 3.93 (3H, s),7.31-7.34 (2H, m), 9.80 (1H, s).

Reference Example 88

[1524] 7-Methoxy-5-(2-methyl-1-propenyl)spiro[benzofuran-2(3H),1′-cyclopentane]

[1525] To a suspension of7-methoxyspiro[benzofuran-2(3H),1′-cyclopentane]-5-carboxaldehyde (10.5g, 45.2 mmol) and isopropyltriphenylphosphonium iodide (31.4 g, 72.6mol) in tetrahydrofuran (150 mL), sodium hydride (60% suspension in oil)(3.26 g, 81.4 mmol) was added, and the mixture was heated under refluxfor 1 hour. The reaction mixture was poured into a 10% aqueous solutionof ammonium chloride, and extracted twice with ethyl acetate. Thecombined organic layer was washed with water and brine, dried overmagnesium sulfate, filtered, and concentrated under reduced pressure.The residue was subjected to a column chromatography on a silica gel(hexane/ethyl acetate, 20:1) to obtain the title compound (11.0 g,yield: 94%).

[1526] An oil.

[1527]¹H NMR (CDCl₃) δ1.54-2.20 (14H, s), 3.17 (2H, s), 3.85 (3H, s),6.20 (1H, s), 6.60 (1H, s), 6.66 (1H, s).

Reference Example 89

[1528] 2-Bromo-3-pentanone

[1529] To a solution of 3-pentanone (172 g, 2.00 mol) in methanol (500mL), bromine (51.1 mL, 1.00 mol) was added dropwise, and the mixture wasstirred at room temperature for 3 hours. The reaction solvent wasconcentrated and distilled off under reduced pressure, and the residuewas treated with an aqueous solution of sodium thiosulfate, andextracted with ethyl acetate. The extract was washed with brine, driedover magnesium sulfate, filtered, and concentrated under reducedpressure. The residue was distilled under reduced pressure to obtain thetitle compound (72.3 g, yield: 44%).

[1530] Boiling point: 65° C./3.3 kPa (25 mmHg)

[1531]¹H NMR (CDCl₃) δ1.12 (3H, t, J=7.4 Hz), 1.75 (3H, t, J=7.0 Hz),2.61 (1H, dq, J=18.0, 7.4 Hz), 2.87 (1H, dq, J=18.0, 7.4 Hz), 4.42 (1H,q, J=7.0 Hz).

Reference Example 90

[1532] 2-(2-Methoxyphenoxy)-3-pentanone

[1533] The title compound was obtained from 2-bromo-3-pentanone by themethod similar to that in Reference Example 83.

[1534] Quantitative.

[1535] An oil.

[1536]¹H NMR (CDCl₃) δ1.07 (3H, t, J=7.4 Hz), 1.51 (3H, t, J=6.8 Hz),2.59 (1H, dq, J=18.0, 7.4 Hz), 2.75 (1H, dq, J=18.0, 7.4 Hz), 3.87 (3H,s), 4.62 (1H, q, J=6.8 Hz), 6.75-6.99 (4H, m).

Reference Example 91

[1537] 1-Methoxy-2-(1-methyl-2-methylenebutoxy)benzene.

[1538] The title compound was obtained from2-(2-methoxyphenoxy)-3-pentanone by the method similar to that inReference Example 84. Yield: 79%.

[1539] An oil.

[1540]¹H NMR (CDCl₃) δ1.07 (3H, t, J=7.2 Hz), 1.50 (3H, t, J=6.6 Hz),2.13 (2H, q, J=7.2 Hz), 3.86 (3H, s), 4.74 (1H, q, J=6.6 Hz), 4.88 (1H,d, J=1.4 Hz), 5.07-5.08 (1H, m), 6.78-6.91 (4H, m).

Reference Example 92

[1541] 2-(2-Ethyl-2-butenyl)-6-methoxyphenol

[1542] The title compound was obtained from1-methoxy-2-(1-methyl-2-methylenebutoxy)benzene by the method similar tothat in Reference Example 85. Yield: 97%.

[1543] An oil.

[1544]¹H NMR (CDCl₃) δ0.98 (3H, t, J=7.6 Hz), 1.61 (3H, d, J=7.0 Hz),2.04 (2H, q, J=7.6 Hz), 3.35 (2H, s), 3.88 (3H, s), 5.19 (1H, q, J=7.0Hz), 5.68 (1H, s), 6.69-6.83 (3H, m).

Reference Example 93

[1545] 2,2-Diethyl-2,3-dihydro-7-methoxybenzofuran

[1546] The title compound was obtained from2-(2-ethyl-2-butenyl)-6-methoxyphenol by the method similar to that inReference Example 86. Yield: 86%.

[1547] An oil.

[1548]¹H NMR (CDCl₃) δ0.94 (6H, t, J=7.4 Hz), 1.78 (4H, q, J=7.4 Hz),3.01 (2H, s), 3.87 (3H, s), 6.71-6.78 (3H, m).

Reference Example 94

[1549] 2,2-Diethyl-2,3-dihydro-7-methoxy-5-benzofurancarboxaldehyde

[1550] The title compound was obtained from2,2-diethyl-2,3-dihydro-7-methoxybenzofuran by the method similar tothat in Reference Example 87. Yield: 59%.

[1551] An oil.

[1552]¹H NMR (CDCl₃) δ0.95 (6H, t, J=7.4 Hz), 1.82 (4H, q, J=7.4 Hz),3.08 (2H, s), 3.93 (3H, s), 7.30, (1H, br s), 7.31 (1H, br s), 9.79 (1H,s).

Reference Example 95

[1553]2,2-Diethyl-2,3-dihydro-7-methoxy-5-(2-methyl-1-propenyl)benzofuran

[1554] The title compound was obtained from2,2-diethyl-2,3-dihydro-7-methoxy-5-benzofurancarboxaldehyde by themethod similar to that in Reference Example 88. Quantitative.

[1555] An oil.

[1556]¹H NMR (CDCl₃) δ0.94 (6H, t, J=7.4 Hz), 1.77 (4H, q, J=7.4 Hz),1.87 (6H, s), 2.99 (2H, s), 3.85 (3H, s), 6.19 (1H, s), 6.59 (1H, s),6.64 (1H, s).

Reference Example 96

[1557] 2,3-Dihydro-7-methoxy-α,α,2,2-tetramethyl-5-benzofuranethanamine

[1558] A mixture of3-(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-2,2-dimethylpropionicacid (5.0 g, 18 mmol), diphenylphosphoryl azide (5.6 g, 20-mmol), andtriethylamine (2.8 mL, 20 mmol) in toluene (100 mL) was heated underreflux for 1 hour. The reaction solution was cooled to room temperature,and then washed with water and brine, dried over magnesium sulfate, andthen the solvent was distilled off under reduced pressure. 6 MHydrochloric acid (30 mL) was added to the resultant residue and themixture was stirred at 60° C. for 1.5 hours. The reaction solution wascooled to room temperature, basified by the addition of 8 M aqueoussolution of sodium hydroxide, and then the organic material wasextracted with diethyl ether. The extract was washed with brine, driedover magnesium sulfate, and then the solvent was distilled off underreduced pressure to obtain the title compound (3.6 g, yield: 80%).

[1559] An oil.

[1560]¹H NMR (CDCl₃) δ1.13 (6H, s), 1.51 (6H, s), 2.58 (2H, s), 3.02(2H, s), 3.86 (3H, s), 6.55 (1H, s), 6.59 (1H, s).

Reference Example 97

[1561]6-Chloro-N-[2-(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-1,1-dimethylethyl]-3-pyridinecarboxamide

[1562] A mixture of2,3-dihydro-7-methoxy-α,α,2,2-tetramethyl-5-benzofuranethanamine (3.7 g,15 mmol), 6-chloronicotinoyl chloride hydrochloride-(3.9 g, 18 mmol),sodium hydrogen carbonate (4.7 g, 56 mmol), tetrahydrofuran (30 mL),toluene (60 mL) and water (30 mL) was stirred at room temperature for14.5 hours. The reaction solution was concentrated under reducedpressure, and the residue was combined with water. The organic materialwas extracted with ethyl acetate. The extract was washed with brine,dried over magnesium sulfate, and then the solvent was distilled offunder reduced pressure. The resultant residue was recrystallized fromethyl acetate-hexane to obtain the title compound (4.9 g, yield: 86%).

[1563] Melting point: 118-119° C.

[1564]¹H NMR (CDCl₃) δ1.48 (6H, s), 1.49 (6H, s), 2.97 (2H, s), 3.04(2H, s), 3.73 (3H, s), 5.72 (1H, br), 6.51 (1H, s), 6.56 (1H, s), 7.38(1H, d, J=8.4 Hz), 7.96 (1H, dd, J=8.4, 2.1 Hz), 8.62 (1H, d, J=2.1 Hz).

Reference Example 98

[1565]N-[2-(2,3-Dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-1,1-dimethylethyl]-1,6-dihydro-1-(6-methyl-2-quinolinyl)-6-oxo-3-pyridinecarboxamide

[1566] A solution of6-chloro-N-[2-(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-1,1-dimethylethyl]-3-pyridinecarboxamide(1.5 g, 3.9 mmol), 6-methylquinoline 1-oxide (3.9 g, 24 mmol), a 25%solution of hydrogen bromide/acetic acid (1.6 mL), and acetic acid (2.4mL) in toluene (13 mL) was heated under reflux for 19.5 hours. Thereaction solution was cooled to room temperature, and then the reactionmixture was poured into water. The mixture was weak-alkalized by theaddition of 8 M aqueous solution of sodium hydroxide, and then theorganic material was extracted with ethyl acetate. The extract waswashed with brine, and then dried over sodium sulfate, and the solventwas distilled off under reduced pressure. The resultant residue waspurified by a column chromatography on a basic silica gel(hexane/chloroform/ethyl acetate, 1:1:1 followed by 1:1:2), andcrystallized from hexane-diisopropyl ether to obtain the title compound(1.2 g, yield: 59%).

[1567] Melting point: 192-193° C.

[1568]¹H NMR (CDCl₃) δ1.45 (12H, s), 2.57 (3H, s), 2.92 (2H, s), 3.03(2H, s), 3.75 (3H, s), 5.60 (1H, br s), 6.54 (2H, d, J=7.4 Hz), 6.65(1H, d, J=9.4 Hz), 7.58-7.70 (3H, m), 7.86 (1H, d, J=8.8 Hz), 7.97 (1H,d, J=8.4 Hz), 8.20 (1H, d, J=8.8 Hz), 8.51 (1H, d, J=2.2 Hz).

Reference Example 99

[1569] 5-(3-Cyanophenyl)-1H-tetrazole-1-acetic acid methyl ester

[1570] 3-(1H-tetrazol-5-yl)benzonitrile (1.77 g, 10 mmol) was dissolvedin N,N-dimethylformamide (20 mL). Sodium carbonate (1.65 g, 12 mmol) andmethyl bromoacetate (1.84 g, 12 mmol) were added to the mixture withcooling in ice. The reaction mixture was allowed to warm to roomtemperature, and stirred for 1 hour. The reaction mixture was combinedwith ice water, and extracted twice with ethyl acetate. The extract waswashed with an aqueous solution of sodium chloride, dried over magnesiumsulfate, filtered, and concentrated under reduced pressure. The residuewas subjected to a column chromatography on a silica gel eluted withhexane/ethyl acetate (2:1), and the objective fraction was collected toconcentrate, and recrystallized from hexane to obtain the title compound(1.98 g, yield: 81%).

[1571] Melting point: 67-69° C.

[1572]¹H NMR (CDCl₃) δ3.86 (3H, s), 5.51 (2H, s), 7.5-8.6 (4H, m).

Reference Example 100

[1573] 2,3-Dihydro-7-methoxy-2,2-dimethyl-5-(2-nitroethenyl)benzofuran

[1574] A mixture of2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofurancarboxaldehyde (17.5 g,84.9 mmol), and ammonium acetate (4.36 g, 56.6 mmol) in nitromethane (85mL) was stirred at 100-105° C. for 1.5 hours. The reaction mixture wasdissolved in ethyl acetate, washed with water and brine, dried overmagnesium sulfate, filtered, and concentrated under reduced pressure.The residue was recrystallized from ethyl acetate-diisopropyl ether toobtain the title compound (17.1 g, yield: 81%).

[1575] Melting point: 154-156° C.

[1576]¹H NMR (CDCl₃) δ1.55 (6H, s), 3.08 (2H, s), 3.92 (3H, s), 6.91(1H, s), 7.04 (1H, s), 7.51 (1H, d, J=13.6 Hz), 7.96 (1H, d, J=13.6 Hz).

Reference Example 101

[1577]N-[2-(2,3-Dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)ethyl]benzamide

[1578] To a solution of2,3-dihydro-7-methoxy-2.2-dimethyl-5-(2-nitroethenyl)benzofuran (16.3 g,65.4 mmol) in tetrahydrofuran (250 mL), lithium aluminum hydride (7.44g, 0.196 mol) was added in portions, and the mixture was heated underreflux for 4 hours. The reaction mixture-was cooled with ice, combinedwith Hyflo Super-Cell (trade name) (37 g), and ethyl acetate (100 mL)was added dropwise, followed by water (15 mL). The resultant mixture wasstirred at the same temperature for 10 minutes, filtered, andconcentrated under reduced pressure to obtain the mixture (12.9 g)containing 2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranethanamine.2.22 g of this material was dissolved in tetrahydrofuran (10 mL). Asolution of sodium carbonate (1.38 g, 13.0 mmol) in water (10 mL) wasadded to the reaction mixture, and then benzoyl chloride (1.28 mL, 11.0mmol) was added dropwise to the mixture with cooling in ice. The mixturewas stirred at the same temperature for 20 minutes. The reaction mixturewas combined with water, and extracted twice with ethyl acetate. Thecombined organic layer was washed with brine, dried over sodium sulfate,filtered, and concentrated under reduced pressure. The residue wassubjected to a column chromatography on a silica gel (hexane/ethylacetate, 10:1 followed by 3:1), and recrystallized from ethylacetate-hexane to obtain the title compound (929 mg, yield 25%).

[1579] Melting point: 137-138° C.

[1580]¹H NMR (CDCl₃) δ1.51 (6H, s), 2.86 (2H, t, J=6.8 Hz), 3.01 (2H,s), 3.61-3.75 (2H, m), 3.83. (3H, s), 6.08-6.22 (1H, m), 6.59 (1H, s),6.65 (1H, s), 7.35-7.55 (3H, m), 7.67-7.75 (2H, m).

Reference Example 102

[1581]2,3-Dihydro-7-methoxy-2,2-dimethyl-5-(2-nitro-1-propenyl)benzofuran

[1582] A solution of2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofurancarboxaldehyde (20.0 g,97.0 mmol), nitroethane (7.70 mL, 107 mmol), piperidine (2.00 mL, 20.2mmol) and acetic acid (5.60 mL, 97.8 mmol) in toluene (37 mL) was heatedunder reflux for 5 hours using Dean-Stark water separator. The reactionsolution was cooled to room temperature. The mixture was separated intowater and ethyl acetate. The organic layer was washed with brine, driedover magnesium sulfate, and then distilled off under reduced pressure.The resultant residue was crystallized from diisopropyl ether to obtainthe title compound (20.9 g, yield: 82%).

[1583] Melting point: 120-121° C.

[1584]¹H NMR (CDCl₃) δ1.55 (6H, s), 2.50 (3H, s), 3.09 (2H, s), 3.91(3H, s), 6.85 (1H, s), 6.96 (1H, s), 8.08 (1H, s).

Reference Example 103

[1585] 2,3-Dihydro-7-methoxy-α,2,2-trimethyl-5-benzofuranethanamine

[1586] To a solution of2,3-dihydro-7-methoxy-2,2-dimethyl-5-(2-nitro-1-propenyl)benzofuran(10.9 g, 41.4 mmol) in tetrahydrofuran (150 mL), lithium aluminumhydride (3.35 g, 88.3 mmol) was added at 0° C. in portions. The reactionsolution was stirred at 0° C. for 15 minutes, and heated under refluxfor 1 hour. The reaction solution was cooled with ice, water was addedin portions, and the insolubles were filtered off. The filtrate wasdried over sodium sulfate, and then the solvent was distilled off underreduced pressure to obtain the title compound (9.00 g, yield: 92%).

[1587] An oil.

[1588]¹H NMR (CDCl₃) δ1.12 (3H, d, J=6.4 Hz), 1.50 (6H, s), 2.40 (1H,dd, J=13.2, 8.4 Hz), 2.66 (1H, dd, J=13.2, 5.2 Hz), 3.01 (2H, s),3.07-3.17 (1H, m), 3.85 (3H, s), 6.56 (1H, s), 6.59 (1H, s).

Reference Example 104

[1589]N-12-(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-1-methylethyl]benzamide

[1590] To a solution of2,3-dihydro-7-methoxy-α,2,2-trimethyl-5-benzofuranethanamine (3.00 g,12.7 mmol) and triethylamine (2.10 mL, 15.1 mmol) in tetrahydrofuran(50.0 mL) and ethyl acetate (50.0 mL), benzoyl chloride (1.50 mL, 12.9mmol) was added dropwise at 0° C. The reaction solution was stirred atroom temperature for 4 hours, and then the solvent was distilled off.The resultant residue was combined with water, and the organic materialwas extracted with ethyl acetate. The extract was washed with brine,dried over magnesium sulfate, and then the solvent was distilled offunder reduced pressure. The resultant residue was recrystallized fromethyl acetate-isopropyl ether to obtain the title compound (1.94 g,yield: 45%).

[1591] Melting point: 141-142° C.

[1592]¹H NMR (CDCl₃) δ1.24 (3H, d, J=6.6 Hz), 1.50 (6H, s), 2.76 (1H,dd, J=13.4, 7.0 Hz), 2.88 (1H, dd, J=13.8, 5.6 Hz), 3.00 (2H, s), 3.80(3H, s), 4.34-4.48 (1H, m), 5.93 (1H, br), 6.58 (1H, s), 6.63 (1H, s),7.37-7.53 (3H, m), 7.71 (2H, dd, J=8.6, 2.0 Hz).

Reference Example 105

[1593]N-[2-(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-1-methylethyl]-4-pyridinecarboxamide

[1594] The title compound was obtained from2,3-dihydro-7-methoxy-α,2,2-trimethyl-5-benzofuranethanamine andisonicotinoyl chloride hydrochloride by the method similar to that inReference Example 97. Yield: 75%.

[1595] Melting point 159-160° C. (ethyl acetate-diisopropyl ether)

[1596]¹H NMR (CDCl₃) δ1.26 (3H, d, J=6.6 Hz), 1.51 (6H, s), 2.71-2.93(2H, m), 3.00 (2H, s), 3.82 (3H, s), 4.34-4.47 (1H, m), 6.00 (1H, br d,J=8.4 Hz), 6.56 (1H, s), 6.61 (1H, s), 7.52-7.55 (2H, m), 8.71-8.74 (2H,m).

Reference Example 106

[1597]2-(Benzoylamino)-3-(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-2-propenoicacid methyl ester

[1598] A suspension of2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofurancarboxaldehyde (12.8 g,62.1 mmol), hippuric acid (12.2 g, 68.1 mmol) and sodium acetate (5.60g, 68.3 mmol) in acetic anhydride (65 mL) was stirred at 100° C. for 1.5hours. The reaction mixture was cooled to room temperature, combinedwith diethyl ether, and crystals were recovered by filtration to obtaina mixture (16.9 g) containing4-[(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)methylene]-2-phenyl-5(4H)-oxazolone. The mother liquor was concentrated again, and crystalswere washed with diisopropyl ether to obtain the same mixture (3.72 g).These were suspended in methanol (100 mL). Sodium carbonate (0.20 g, 1.9mmol) was added to the suspension and the mixture heated under refluxfor 3 hours. The reaction mixture was concentrated under reducedpressure and the residue was partitioned between ethyl acetate andwater. The aqueous layer was separated, the organic layer was washed andconcentrated under reduced pressure. The residue was crystallized frommethanol-diisopropyl ether to obtain the title compound (10.5 g, yield:44%).

[1599] Melting point: 184-186° C.

[1600]¹H NMR (CDCl₃) δ1.50 (6H, s), 2.99 (2H, s), 3.66 (3H, s), 3.85(3H, s), 7.00 (2H, s), 7.43-7.64 (4H, m), 7.67 (1H, br s), 7.86-7.95(2H, m).

Reference Example 107

[1601]α-(Benzoylamino)-2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranpropanoicacid methyl ester

[1602] To a solution of2-(benzoylamino)-3-(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-2-propenoicacid methyl ester (11.5 g, 30.2 mmol) in tetrahydrofuran (100 mL), 10%palladium on carbon (50% hydrate) (1.2 g) was added, and the mixture wasstirred at 50° C. for 4 hours under hydrogen atmosphere. The catalystwas filtered off and filtrate was concentrated under reduced pressure.The resultant crystals were washed with diisopropyl ether to obtain thetitle compound (10.1 g, yield: 87%).

[1603] Melting point: 160-162° C.

[1604]¹H NMR (CDCl₃) δ1.50 (6H, s), 2.98 (2H, s), 3.15 (1H, dd, J=13.9,5.1 Hz), 3.23 (1H, dd, J=13.9, 5.9 Hz), 3.75 (3H, s), 3.78 (3H, s), 5.04(1H, dt, J=7.5, 5.5 Hz), 6.48 (1H, s), 6.53 (1H, s), 6.59 (1H, br d,J=7.5 Hz), 7.36-7.57 (3H, m), 7.71-7.79 (2H, m).

Reference Example 108

[1605] 2-Amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzoicacid methyl ester

[1606] To a solution of methyl 5-iodoanthranilate (2.87 g, 10.0 mmol)and triethylamine (4.2 mL. 30 mmol) in 1,4-dioxane (20 mL),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)dichloromethane complex (82 mg, 0.10 mmol) was added and4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.7 mL, 25 mmol) was addeddropwise. The resultant mixture was stirred at 80° C. for 14 hours undernitrogen atmosphere. The reaction mixture was combined with water, andextracted twice with ethyl acetate.

[1607] The combined organic layer was washed with water and brine,filtered through a silica gel (eluting with ethyl acetate), andconcentrated under reduced pressure. The residue was subjected to acolumn chromatography on a silica gel (hexane/ethyl acetate, 5:1), andrecrystallized from ethyl acetate-hexane to obtain the title compound(1.45 9 yield: 52%).

[1608] Melting point: 110-112° C.

[1609]¹H NMR (CDCl₃) δ1.33 (12H, s), 3.86 (3H, s), 5.96 (2H, br s), 6.63(1H, d, J=8.3 Hz), 7.67 (1H, dd, J=8.3, 1.5 Hz), 8.33 (1H, d, J=1.5 Hz).

Reference Example 109

[1610] 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)benzoic acidethyl ester

[1611] To a solution of ethyl 4-iodobenzoate (2.76 g, 10.0 mol) andtriethylamine (4.2 mL, 30 mol) in 1,4-dioxane (20 mL),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane complex (82 mg, 0.10 mmol) was added, and4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.2 mL, 22 mmol) was addeddropwise. The resultant mixture was stirred at 80° C. for 14 hours undernitrogen atmosphere, and at 100° C. for 3 hours. The reaction mixturewas combined with water, and extracted twice with ethyl acetate. Thecombined organic layer was washed with water and brine, dried throughsodium sulfate-silica gel (eluting with ethyl acetate), and concentratedunder reduced pressure. The residue was subjected to a columnchromatography on a silica gel (hexane/ethyl acetate, 20:1) to obtainthe title compound (2.26 g, yield: 82%).

[1612] An oil.

[1613]¹H NMR (CDCl₃) δ1.36 (12H, s), 1.40 (3H, t, J=7.1 Hz), 4.39 (2H,q, J=7.1 Hz), 7.86 (2H, d, J=8.4 Hz), 8.03 (2H, d, J=8.4 Hz).

Reference Example 110

[1614]β-(Benzoylamino)-2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranpropanol

[1615] To a suspension ofα-(benzoylamino)-2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranpropanoicacid methyl ester (3.84 g, 10.0 mmol) in tetrahydrofuran (30 mL), sodiumborohydride (90%) (1.26 g, 30 mmol) was added. Methanol (5 mL) was addeddropwise to the resultant mixture while heating under reflux over 30minutes, and then the mixture was heated under reflux for 5 minutes. Thereaction mixture was allowed to cool, combined with water, and extractedtwice with ethyl acetate. The combined organic layer was washed twicewith water and concentrated under reduced pressure. The residue wasrecrystallized from methanol-diisopropyl ether to obtain the titlecompound (2.65 g, yield: 75%).

[1616] Melting point: 155-158° C.

[1617]¹H NMR (CDCl₃) δ1.50 (6H, s), 2.91 (2H, d, J=7.2 Hz), 3.00 (2H,s), 3.66-3.87 (2H, m), 3.82 (3H, s), 4.20-4.38 (1H, m), 6.37-6.48 (1H,m), 6.63 (1H, s), 6.67 (1H, s), 7.35-7.55 (3H, m), 7.65-7.73 (2H, m).

Reference Example 111

[1618]2-(Benzoylamino)-3-(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)propylacetate

[1619] To a suspension ofβ-(Benzoylamino)-2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranpropanol(3.13 g, 8.81 mmol) and 4-(dimethylamino)pyridine (108 mg, 0.884 mmol)in tetrahydrofuran (30 mL), triethylamine (1.84 mL, 13.2 mmol) andacetic anhydride (1.16 mL, 12.3 mmol) was added dropwise, and themixture was stirred at room temperature for 20 minutes. The reactionmixture was combined with water and extracted twice with ethyl acetate.The combined organic layer was washed twice with water and concentratedunder reduced pressure. The residue was recrystallized frommethanol-diisopropyl ether to obtain the title compound (3.26 g, yield:93%).

[1620] Melting point: 141-142° C.

[1621]¹H NMR (CDCl₃) δ1.50 (6H, s), 2.11 (3H, s), 2.79 (1H, dd, J=13.7,8.3 Hz), 2.93-3.05 (1H, m), 3.00 (2H, s), 3.82 (3H, s), 4.15 (1H, dd,J=11.4, 4.1 Hz), 4.28 (1H, dd, J=11.4, 6.2 Hz), 4.47-4.64 (1H, m), 6.43(1H, br d, J=8.4 Hz), 6.61 (1H, s), 6.64 (1H, s), 7.38-7.57 (3H, m),7.70-7.78 (2H, m).

Reference Example 112

[1622]N-[3′-(1,2,3,4,8,9-Hexahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-3-yl]acetamide

[1623] The title compound was obtained fromN-[3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-3-yl]acetamideby the method similar to that in Reference Example 10. Yield: 84%.

[1624] Melting point: 162-165° C. (ethyl acetate-hexane)

[1625]¹H NMR (CDCl₃) δ1.18 (3H, s), 1.21 (3H, s), 1.25 (3H, s), 1.34(3H, s), 1.85 (1H, d, J=15.8 Hz), 2.20 (3H, s), 2.47 (1H, d, J=15.8 Hz),2.56 (1H, d, J=15.4 Hz), 2.83 (1H, d, J=15.4 Hz), 3.87 (3H, s), 5.00(1H, s), 6.50 (1H, s), 7.15-7.66 (9H, m).

Reference Example 113

[1626] 3-Cyano-N-(3,5-dichloro-4-pyridinyl)benzamide

[1627] A mixture of 3-cyanobenzoic acid (2.71 g, 18.4 mmol) and thionylchloride (10 mL) was heated under reflux for 1.5 hours. The reactionsolution was concentrated under reduced pressure, and the residue wascombined with toluene and concentrated under reduced pressure again. Asuspension of 4-amino-3,5-dichloropyridine (2.50 g, 15.3 mmol) intetrahydrofuran (30 mL) was cooled with ice. Then sodium hydride (66%suspension in oil) (1.34 g, 36.7 mmol) followed by the concentratedresidue prepared previously were added to the suspension. The mixturewas stirred at room temperature for 2 hours, poured into ice water, andthen extracted with ethyl acetate. The extract was washed with water andconcentrated under reduced pressure. The residue was recrystallized fromethyl acetate-hexane to obtain the title compound (0.45 g, yield: 11%).The mother liquor was concentrated, the residue was subjected to acolumn chromatography on a basic silica gel (ethyl acetate/methanol,19:1),and then recrystallized from ethyl acetate-hexane to obtain theadditional title compound (0.66 g, yield: 15%).

[1628] Melting point: 242-244° C.

[1629]¹H NMR (CDCl₃+DMSO-d₆) δ7.65 (1H, t, J=8.0 Hz), 7.87 (1H, dd,J=1.4, 8.0 Hz), 8.34 (1H, dd, J=1.4, 8.0 Hz), 8.49 (1H, s), 8.58 (2H,s), 10.24 (1H, br s).

Reference Example 114

[1630] 3-Cyano-N-(3,5-dichloro-1-oxido-4-pyridinyl)benzamide

[1631] A suspension of 3-cyano-N-(3,5-dichloro-4-pyridinyl)benzamide(1.06 g, 3.78 mmol) and m-chloroperbenzoic acid (70%) (2.80 g, 11.3mmol) in ethyl acetate (20 mL) was stirred at 50° C. for 15 hours undernitrogen atmosphere. The reaction mixture was combined with water and anaqueous solution of sodium thiosulfate, and extracted with ethylacetate. The extract was washed with water and then concentrated underreduced pressure. The residue was subjected to a column chromatographyon a silica gel (ethyl acetate/methanol, 49:1 to 23:2) andrecrystallized from ethyl acetate-hexane to obtain the title compound(0.88 g, yield: 79%).

[1632] Melting point: 234-235° C.

[1633]¹H NMR (CDCl₃+DMSO-d₆) δ7.65 (1H, t, J=8.0 Hz), 7.87 (1H, d, J=8.0Hz), 8.26 (2H, s), 8.32 (1H, d, J=8.0 Hz), 8.47 (1H, s), 10.16 (1H, brs).

Reference Example 115

[1634]1-(7-Ethoxy-2,3-dihydro-2,2-dimethyl-5-benzofuranyl)-2-methyl-1-propanol

[1635] A solution of7-ethoxy-2,3-dihydro-2,2-dimethyl-5-benzofurancarboxaldehyde (30.0 g,0.136 mol) in tetrahydrofuran (50 mL) was cooled with ice, to this asuspension of the Grignard reagent prepared from 2-bromopropane (25.1 g,0.204 mol) and magnesium (4.97 g, 0.204 mol) in tetrahydrofuran (50 mL)was added, and the mixture was stirred at room temperature for 1 hour.The reaction solution was poured into ice water and extracted with ethylacetate. The extract was, washed with water and concentrated underreduced pressure. The residue was crystallized from ethyl acetate-hexaneto obtain the title compound (29.8 g, yield: 83%).

[1636] Melting point: 100-101° C.

[1637]¹H NMR (CDCl₃) δ0.77 (3H, d, J=6.6 Hz), 1.02 (3H, d, J=6.6 Hz),1.42 (3H, t, J=7.0 Hz), 1.51 (6H, s), 1.77 (1H, d, J=6.6 Hz), 1.80-1.99(1H, m), 3.00 (2H, s), 4.12 (2H, q, J=7.0 Hz), 4.21 (1H, dd, J=2.8-Hz,7.2 Hz), 6.70 (2H, s).

Reference Example 116

[1638] 1-Ethoxy-2-(2-methyl-2-propenyloxy)benzene

[1639] A suspension of 2-ethoxyphenol(5.00 g, 36.2 mmol),3-chloro-2-methyl-1-propene (3.93 mL, 39.8 mmol)-potassium carbonate(5.75 g, 41.6 mmol) and potassium iodide (0.60 g, 3.62 mmol) inN,N-dimethylformamide (25 mL) was stirred at 90° C. for 1.5 hours undernitrogen atmosphere. The reaction mixture was allowed to cool to roomtemperature, combined with water, and then extracted with ethyl acetate.The extract was washed with 1 M aqueous solution of sodium hydroxide andwater, and then concentrated under reduced pressure to obtain the titlecompound (5.90 g, yield: 85%).

[1640] An oil.

[1641]¹H NMR (CDCl₃) δ1.44 (3H, t, J=6.9 Hz), 1.84 (3H, s), 4.09 (2H, q,J=6.9 Hz), 4.50 (2H, s), 4.97 (1H, s), 5.10 (1H, s), 6.88-6.91 (4H, m).

Reference Example 117

[1642] 2-Ethoxy-6-(2-methyl-2-propenyl)phenol

[1643] A solution of 1-ethoxy-2-(2-methyl-2-propenyloxy)benzene (5.80 g,30.2 mmol) in N,N-diethylaniline (12 mL) was stirred at 205° C. for 3.5hours under nitrogen atmosphere. The reaction mixture was allowed tocool to room temperature, cooled with ice, combined with 2 Mhydrochloric acid (39 mL), and then extracted with ethyl acetate. Theextract was washed with water and then concentrated under reducedpressure to obtain the title compound (5.60 g, yield: 97%).

[1644] An oil.

[1645]¹H NMR (CDCl₃) δ1.44 (3H, t, J=7.0 Hz), 1.75 (3H, s), 3.36 (2H,s), 4.10 (2H, q, J=7.0 Hz), 4.69 (1H, s), 4.80 (1H, s), 6.65-6.79 (3H,m).

Reference Example 118

[1646] 7-Ethoxy-2,3-dihydro-2,2-dimethylbenzofuran

[1647] To a solution of 2-ethoxy-6-(2-methyl-2-propenyl)phenol (5.50 g,28.6 mmol) in toluene (30 mL), boron trifluoride diethyl ether complex(3.99 mL, 31.5 mmol) was added, and the mixture was stirred at 100° C.for 1.5 hours under nitrogen atmosphere. The reaction solution wasallowed to cool to room temperature, combined with 1 M aqueous solutionof sodium hydroxide (30 mL), and then extracted with hexane. The extractwas washed with 1 M aqueous solution of sodium hydroxide and water, andthen concentrated under reduced pressure. The residue was subjected to acolumn chromatography on a silica gel to obtain the title compound (2.90g, yield: 53%).

[1648] An oil.

[1649]¹H NMR (CDCl₃) δ1.43 (3H, t, J=7.0 Hz), 1.51′(6H, s), 3.02 (2H,s), 4.12 (2H, q, J=7.0 Hz), 6.71-6.78 (3H, m).

Reference Example 119

[1650] 5-Bromo-7-ethoxy-2,3-dihydro-2,2-dimethylbenzofuran

[1651] A solution of 7-ethoxy-2,3-dihydro-2,2-dimethylbenzofuran (10.0g, 52.0 mmol) in toluene (50 mL) was cooled to −4020 C., and bromine(8.72 g, 54.6 mmol) was added dropwise. The reaction solution wasstirred at the same temperature for 20 minutes, combined with an aqueoussolution of sodium thiosulfate, and then extracted with hexane. Theextract was washed with water and then concentrated under reducedpressure. The residue was subjected to a column chromatography on asilica gel (hexane/ethyl acetate, 19:1) to obtain the title compound(13.6 g, yield: 96%).

[1652] Melting point: 55-58 °C. (pentane)

[1653]¹H NMR (CDCl₃) δ1.43 (3H, t, J=7.0 Hz), 1.50 (6H, s), 3.00 (2H,s), 4.09 (2H, q, J=7.0 Hz), 6.83-6.85 (1H, m), 6.86-6.88 (1H, m).

Reference Example 120

[1654]7-Ethoxy-2,3-dihydro-2,2-dimethyl-5-(2-methyl-2-propenyl)benzofuran

[1655] A solution of 5-bromo-7-ethoxy-2,3-dihydro-2,2-dimethylbenzofuran(3.60 g, 13.3 mmol) in tetrahydrofuran (30 mL) was cooled to −78° C., a1.57 M solution of n-butyllithium in hexane (9.30 mL, 14.6 mmol) wasadded dropwise, and the mixture was stirred at the same temperature for15 minutes. To this copper (I) iodide (1.39 g, 7.32 mmol) was added, andthe mixture was stirred under ice cooling for 15 minutes. After coolingthe mixture to −40° C., 3-chloro-2-methyl-1-propene (1.44 mL, 14.6 mmol)was added dropwise, and the mixture was stirred under ice cooling for 15minutes. The reaction mixture was combined with water and extracted withethyl acetate. The extract was washed with water and then concentratedunder reduced pressure. The residue was subjected to a columnchromatography on a silica gel (hexane/ethyl acetate, 19:1) to obtainthe title compound (2.34 g, yield: 71%).

[1656] An oil.

[1657]¹H NMR (CDCl₃) δ1.41 (3H, t, J=7.0 Hz), 1.50 (6H, s), 1.68 (3H,s), 2.99 (2H, s), 3.22 (2H, s), 4.11 (2H, q, J=7.0 Hz), 4.73 (1H, s),4.78 (1H, s), 6.56 (1H, s), 6.58 (1H, s).

Reference Example 121

[1658] 3-Cyano-N-methylbenzenesulfonamide

[1659] To a suspension of methylamine hydrochloride (1.67 g, 24.8-mmol)in pyridine (6 mL), 3-cyanobenzenesulfonyl chloride (5.00 g, 24.8 mmol)was added with cooling in ice, and the mixture was stirred at roomtemperature for 3 hours. The reaction mixture was poured into ice water,acidified with 1 M hydrochloric acid, and extracted twice with ethylacetate. The combined organic layer was washed with 1 M hydrochloricacid, water and brine, dried over magnesium sulfate, and concentratedunder reduced pressure to obtain the title compound (4.49 g, yield: 92%)as crystals.

[1660]¹H NMR (CDCl₃) δ2.73 (3H, d, J=5.4 Hz), 4.51 (1H, br), 7.69 (1H,t, J=7.8 Hz), 7.88 (1H, dt, J=7.8, 1.5, Hz), 8.00 (1H, dt, J=7.8, 1.5Hz), 8.17 (1H, t, J=1.5 Hz).

Reference 122

[1661] N-[-3-[[(3-Cyanobenzene)sulfonyl]amino]phenyl]acetamide

[1662] To a solution of 3′-aminoacetanilide (745 mg, 4.96 mmol) intetrahydrofuran (10 mL), triethylamine (0.76 mL, 5.46 mmol) and3-cyanobenzenesulfonyl chloride (1.00 g, 4.96 mmol) were added, and themixture was stirred at room temperature for 3 hours. Water was pouredinto the reaction mixture, which was then extracted twice with ethylacetate. The combined organic layer was washed with brine, dried overmagnesium sulfate, filtered, and concentrated under reduced pressure.The residue was subjected to a column chromatography on a silica gel(hexane/ethyl acetate, 1:1 followed by 1:2) to obtain the title compound(1.39 g, yield: 89%) as crystals.

[1663]¹H NMR (CDCl₃) δ2.23 (3H, s), 6.97-7.03 (2H, m), 7.21 (1H, d,J=8.2 Hz), 7.51-7.64 (2H, m), 7.73-7.81 (2H, m), 7.96-8.10 (2H, m).

Reference Example 123

[1664] 2[[(3-Cyanobenzene) sulfonyl]amino]acetamide

[1665] To a solution of 3-cyanobenzensulfonyl chloride (538 mg, 2.67mmol) in pyridine (3 mL), glycinamide hydrochloride (301 mg, 2.67 mmol)was added, and the mixture was stirred at room temperature for 1 hour,at 60° C. for 2 hours, and at 90° C. for 4 hours. Water was poured intothe reaction mixture, which was then extracted twice with ethyl acetate.The combined organic layer was washed with 1 M hydrochloric acid andbrine, dried over sodium sulfate, filtered, and concentrated underreduced pressure to obtain the title compound (180 mg, yield: 28%) ascrystals.

[1666]¹H NMR (CDCl₃) δ3.57 (2H, d, J=5.7 Hz), 6.25 (1H, br s), 7.00 (1H,br s), 7.68 (1H, t, J=7.8 Hz), 7.76 (1H, t, J=5.7 Hz), 7.87 (1H, dd,J=7.8, 1.4 Hz), 8.12 (1H, dd, J=7.8, 1.4 Hz), 8.14 (1H, t, J=1.4 Hz).

Reference Example 124

[1667] 3-Cyano-N-(hexahydro-2-oxo-1H-azepin-3-yl)benzenesulfonamide

[1668] To a solution of 3-aminohexahydro-2H-azepin-2-one (305 mg, 2.38mmol) in tetrahydrofuran (3 mL), 1 M aqueous solution of sodiumhydroxide (2 mL) and 3-cyanobenzenesulfonyl chloride (400 mg, 1.98 mmol)was added, and the mixture was stirred at room temperature for 3 hours.Diisopropyl ether was poured into the reaction mixture, and precipitatedcrystals were filtered off and washed with water and diisopropyl etherto obtain the title compound (360 mg, yield: 62%) as crystals.

[1669]¹H NMR (CDCl₃) δ1.34-1.90 (4H, m), 2.02-2.16 (2H, m), 3.11-3.25(2H, m), 3.87-3.92 (1H, m), 5.99 (1H, br s), 6.25 (1H, br s), 7.65 (1H,dd, J=8.4, 7.8 Hz), 7.84 (1H, ddd, J=7.8, 1.6, 1.4 Hz), 8.04 (1H, ddd,J=8.4, 1.6, 1.4 Hz), 8.15 (1H, dd, J=1.6, 1.4 Hz).

Reference Example 125

[1670] 2,3-Dihydro-7-methoxy-2,2-dimethyl-5-benzofuranacetonitrile

[1671] Potassium tert-butoxide (11.8 g, 105 mmol) was suspended indimethoxyethane (75 mL), cooled at a temperature not higher than −7020C. Then toluenesulfonylmethyl isocyanide (10.2 g, 52.5 mmol) was addedto the mixture and the mixture was stirred at a temperature not higherthan −70° C. for 30 minutes. A solution of2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofurancarboxaldehyde (10.4 g,50 mmol) in dimethoxyethane (25 mL) was added dropwise to the reactionmixture for 10 minutes. After stirring at a temperature not higher than−70° C. for 30 minutes, the mixture was combined with methanol (75 mL),allowed to warm to room temperature, and heated under reflux further for2 hours. The reaction solution was concentrated under reduced pressure,and iced water was poured into the residue, which was then extractedtwice with ethyl acetate. The extract was washed with brine, dried overmagnesium sulfate, filtered, and concentrated under reduced pressure.Diethyl ether was poured into the residue, and precipitated crystalswere recovered by-filtration, washed with diethyl ether, and dried toobtain the title compound (6.85 g, yield: 63%).

[1672]¹H NMR (CDCl₃) δ1.51 (6H, s), 3.03 (2H, s), 3.67 (2H, s), 3.87(3H, s), 6.66 (1H, s), 6.74 (1H, s).

Reference Example 126

[1673]2-(2,3-Dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-2-methylpropanenitrile

[1674] A 60% sodium hydride in oil (2.92 g, 73 mmol) was suspended inN,N-dimethylformamide (75 mL), and2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranacetonitrile (7.95 g,36.5 mmol) was added thereto in portions with cooling in ice. Themixture was stirred at room temperature for 30 minutes, and iodomethane(13 g, 92 mmol) was added dropwise with cooling in ice again over 5minutes. After stirring at room temperature for 3 hours, the reactionmixture was poured into ice water, and extracted twice with ethylacetate. The extract was washed with brine, dried over magnesiumsulfate, filtered, and concentrated under reduced pressure. The residuewas subjected to a column chromatography on a silica gel eluting withhexane/ethyl acetate (5:1), and the desired fraction was collected andconcentrated to obtain the title compound (8.6 g, yield 96%).

[1675] An oil.

[1676]¹H NMR (CDCl₃) δ1.52 (6H, s), 1.71 (6H, s), 3.64 (2H, s), 3.90(3H, s), 6.82 (1H, s), 6.87 (1H, s).

Reference Example 127

[1677]2-(2,3-Dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-2-methylpropanamide

[1678]2-(2,3-Dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-2-methylpropanenitrile(8.6 g, 35 mmol) was dissolved in methanol (105 mL). 1 M aqueoussolution of sodium hydroxide (52 mL) and 30% aqueous solution ofhydrogen peroxide (7.94 mL) were added to the mixture and the mixturewas stirred at room temperature for 18 hours. Methanol was distilled offunder reduced pressure, and the residue was extracted twice with ethylacetate. The extract was washed with brine, dried over magnesiumsulfate, filtered, and concentrated under reduced pressure. The residuewas combined with diethyl ether, and crystallized to obtain the titlecompound (7.73 g, yield: 84%).

[1679] Melting point: 112-113° C.

[1680]¹H NMR (CDCl₃) δ1.51 (6H, s), 1.56 (6H, s), 3.03 (2H, s), 3.87(3H, s), 5.30 (1H, br), 5.45 (1H, br), 6.73 (1H, s), 6.81 (1H, s).

Reference Example 128

[1681]N-[2-(2,3-Dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-2-methylpropyl]benzamide

[1682] To a suspension of lithium aluminum hydride (0.285 g, 7.5 mmol)in tetrahydrofuran (15 mL),2-(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-2-methylpropanamide(0.791 g, 3 mmol) was added in nitrogen flow. After stirring at roomtemperature for 30 minutes, the mixture was heated under reflux furtherfor 1 hour. The mixture was combined with ethyl acetate (15 mL) withcooling in ice stirred for 30 minutes, and combined with ice water (15mL), the insolubles were removed using Celite, and the filtrate wasextracted twice with ethyl acetate. The extract was washed with brine,dried over magnesium sulfate, filtered, and concentrated under reducedpressure. The residue was dissolved in tetrahydrofuran (10 mL). Pyridine(0.73 mL, 9 mmol) and benzoyl chloride (0.53 mL, 4.5 mmol) were added tothe mixture and the mixture was stirred at room temperature for 15hours. The reaction solution was combined with ethyl acetate (20 mL),washed with water and an aqueous solution of sodium chloride, dried overmagnesium sulfate, filtered, and concentrated under reduced pressure.The residue was subjected to a column chromatography on a silica geleluting with hexane/ethyl acetate (3:1), and the desired fraction wascollected and concentrated to obtain the title compound (0.572 g, yield:53%), which was then recrystallized from diethyl ether/hexane (1:1).

[1683] Melting point: 109-110° C.

[1684]¹H NMR (CDCl₃) δ1.38 (6H, s), 1.53 (6H, s), 3.04 (2H, s), 3.61(2H, d, J=6 Hz), 3.88 (3H, s), 5.80 (1H, br), 6.76 (1H, s), 6.81 (1H,s), 7.3-7.7 (5H, m).

Reference Example 129

[1685]3-Cyano-N-[2-(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-2-methylpropyl]benzamide

[1686] To a suspension of lithium aluminum (0.475 g, 12.5 mmol) intetrahydrofuran (33 mL),2-(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-2-methylpropanamide(1.32 g, 5 mmol) was added in nitrogen flow. After stirring at roomtemperature for 30 minutes, the mixture was heated under reflux furtherfor 1 hour. The mixture was combined with ethyl acetate (25 mL) withcooling in ice, stirred for 30 minutes, combined with ice water (15 mL),the insolubles were removed using Celite, and the filtrate was extractedtwice with ethyl acetate. The extract was washed with an aqueoussolution of sodium chloride, dried over magnesium sulfate, filtered, andconcentrated under reduced pressure. The residue was dissolved intetrahydrofuran (10 mL), added to a solution of activated ester whichhad been prepared by stirring 3-cyanobenzoic acid (0.883 g, 6 mmol) andN,N′-carbonyldiimidazole. (0.892 g, 5.5 mmol) at room temperature for 30minutes, and stirred at room temperature for 15 hours. The reactionsolution was combined with ethyl acetate (33 mL), washed with water andan aqueous solution of sodium chloride, dried over magnesium sulfate,filtered, and concentrated under reduced pressure. The residue wassubjected to a column chromatography on a silica gel eluting withhexane/ethyl acetate (2:1), and the desired fraction was collected andconcentrated under reduced pressure to obtain the title compound (0.955g, yield: 50%).

[1687] An oil.

[1688]¹H NMR (CDCl₃) δ1.39 (6H, s), 1.52 (6H, s), 3.06 (2H, s), 3.62(2H, d, J=6 Hz), 3.88 (3H, s), 5.80 (1H, br), 6.75 (1H, s), 6.81 (1H,s), 7.4-8.0 (4H, m).

Reference Example 130

[1689][[2-(2,3-Dihydro-7-methoxy-2,2-dimethyl-1-benzofuran-5-yl)-2-methylpropyl]amino]oxoaceticacid ether ester

[1690] To a suspension of lithium aluminum hydride (0.285 g, 7.5 mmol)in tetrahydrofuran (20 mL),2-(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-2-methylpropanamide(0.791 g, 3 mmol) was added in nitrogen flow. After stirring at roomtemperature for 30 minutes, the mixture was heated under reflux furtherfor 1 hour. The mixture was combined with ethyl acetate (15 mL) withcooling in ice, stirred for 30 minutes, combined with ice water (15 mL),the insolubles were removed using Celite, and the filtrate was extractedtwice with ethyl acetate. The extract was washed with an aqueoussolution of sodium chloride, dried over magnesium sulfate, filtered, andconcentrated under reduced pressure. The residue was dissolved intetrahydrofuran (10 mL). Pyridine (0.73 mL, 9 mol) and ethylchloroglyoxylate (0.615 g, 4.5 mmol) were added to the mixture and themixture was stirred at room temperature for 15 hours. The reactionsolution was combined with ethyl acetate (20 mL), washed with water andan aqueous solution of sodium chloride, dried over magnesium sulfate,filtered, and concentrated under reduced pressure. The residue wassubjected to a column chromatography on a silica gel eluting withhexane/ethyl acetate (2:1), and the desired fraction was collected andconcentrated to obtain the title compound (0.51 g, yield: 49%).

[1691] An oil.

[1692]¹H NMR (CDCl₃) δ1.26 (3H, t, J=7 Hz), 1.34 (6H, s), 1.52 (6H, s),3.03 (2H, s), 3.48 (2H, d, J=6 Hz), 3.88 (3H, s), 4.13 (2H, g, J=7 Hz),6.69 (1H, s), 6.74 (1H, s), 6.92 (1H, br).

Reference Example 131

[1693]3-Bromo-N-[2-(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-2-methylpropyl]benzamide

[1694] To a solution of2-(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-2-methylpropanamide(1.00 g, 3.80 mmol) in tetrahydrofuran (10 mL), lithium aluminum hydride(80%) (0.36 g, 7.6 mmol) was added with cooling in ice, and the mixturewas heated under reflux for 1 hour. The reaction mixture was cooled withice, Hyflo Super-Cell (trade name) (1.5 g) was added thereto, ethylacetate (1 mL) and water (0.5 mL) were added dropwise thereto slowly,and ethyl acetate was added to suspend, and the mixture was filtered andconcentrated under reduced pressure to obtain2-(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-2-methylpropanamine.

[1695] This was dissolved in tetrahydrofuran (8 mL) and triethylamine(0.64 mL, 4.6 mmol) was added to the mixture. The resultant mixture wascooled with ice, 3-bromobenzoyl chloride (0.55 mL, 4.2 mmol) was addeddropwise thereto, and the mixture was stirred at the same temperaturefor 10 minutes. The reaction mixture was combined with water andextracted twice with chloroform. The combined organic layer was washedwith brine, dried over magnesium sulfate, filtered, and concentratedunder reduced pressure. The residue was crystallized fromchloroform-diisopropyl ether to obtain the title compound (1.41 g,yield: 86%).

[1696] Melting point: 157-163° C.

[1697]¹H NMR (CDCl₃) δ1.38 (6H, s), 1.53 (6H, s), 3.06 (2H, s), 3.58(2H, d, J=5.8 Hz), 3.89 (3H, s), 5.65-5.80 (1H, m), 6.76 (1H, s), 6.80(1H, s), 7.21-7.31 (1H, m), 7.51 (1H, dt, J=7.8, 2.5 Hz), 7.59 (1H, ddd,J=7.8, 2.0, 1.1 Hz), 7.73 (1H, t, J=1.8 Hz).

Reference Example 132

[1698] (4-Iodophenyl)carbamic acid phenylmethyl ester

[1699] To a solution of 4-iodoaniline (4.38 g, 20.0 mmol) intetrahydrofuran, a solution of sodium carbonate (2.65 g, 25.0 mmol) inwater (15 mL) was added, benzyl chloroformate (3.1 mL, 22 mmol) wasadded dropwise with cooling in ice, and the mixture was stirred at thesame temperature for 15 minutes. The reaction mixture was combined withwater and extracted twice with ethyl acetate. The combined organic layerwas washed with water and brine, dried over magnesium sulfate, treatedwith activated charcoal, filtered, and concentrated under reducedpressure. The residue was recrystallized from diisopropyl ether toobtain the title compound (4.71 g, yield: 67%).

[1700] Melting point: 132-134° C.

[1701]¹H NMR (CDCl₃) δ5.20 (2H, s), 6.64 (1H, br s), 7.18 (2H, d, J=8.8Hz), 7.33-7.45 (5H, m), 7.60 (2H, d, J=8.8 Hz).

Reference Example 133

[1702] [4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamicacid phenylmethyl ester

[1703] To a solution of (4-iodophenyl)carbamic acid phenylmethyl ester(6.50 g, 18.4 mol) and triethylamine (7.7 mL, 55 mmol) in 1,4-dioxane(35 mL), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane complex (150 mg, 0.184 mmol) was added, and4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.9 mL, 41 mmol) was addeddropwise. The resultant mixture was stirred at 85° C. for 2.5 hoursunder nitrogen atmosphere. The reaction mixture was cooled with ice,combined with water, and extracted twice with ethyl acetate. Thecombined organic layer was washed with water and brine, dried throughsodium sulfate silica gel (eluting with ethyl acetate), and concentratedunder reduced pressure. The residue was subjected to a columnchromatography on a silica gel (hexane/ethyl acetate, 10:1 followed by4:1) to obtain the title compound (5.47 g, yield: 84%).

[1704] An oil.

[1705]¹H NMR (CDCl₃) δ1.33 (12H, s), 5.20 (2H, s), 6.76 (1H, br s),7.25-7.52 (7H, m), 7.75 (2H, d, J=8.4 Hz).

Reference Example 134

[1706]N-[3′-(1,2,3,4,8,9-Hexahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-yl]acetamide

[1707] The title compound was obtained fromN-[3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-yl]acetamideby the method similar to that in Reference Example 10. Yield: 88%.

[1708] Amorphous.

[1709]¹H NMR (CDCl₃) δ1.19 (3H, s), 1.20 (3H, s), 1.25 (3H, s), 1.35(3H, s), 1.85 (1H, d, J=15.7 Hz), 2.19 (3H, s), 2.48 (1H, d, J=15.7 Hz),2.57 (1H, d, J=15.6 Hz), 2.83 (1H, d, J=15.6 Hz), 3.87 (3H, s), 5.00(1H, s), 6.50 (1H, s), 7.17 (1H, d, J=7.4 Hz), 7.30-7.60 (8H, m).

Reference Example 135

[1710]3′-(1,2,3,4,8,9-Hexahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-amine

[1711] The title compound was obtained from3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-amineby the method similar to that in Reference Example 10. Yield: 91%.

[1712] Amorphous.

[1713]¹H NMR (CDCl₃) δ1.18 (3H, s), 1.20 (3H, s), 1.25 (3H, s), 1.34(3H, s), 1.87 (1H, d, J=15.4 Hz), 2.43-2.60 (2H, m), 2.82. (1H, d,J=15.4 Hz), 3.72 (2H, br s), 3.87 (3H, s), 4.98 (1H, s), 6.49 (1H, s),6.73 (2H, d, J=8.4 Hz), 7.11 (1H, dt, J=7.3, 1.5 Hz), 7.25-7.47 (5H, m).

Reference Example 136

[1714] 3-Cyano-N-methylbenzamide

[1715] A solution of 3-cyanobenzoic acid (2.00 g, 13.6 mmol) intetrahydrofuran (10 mL) was cooled with ice, N,N′-carbonyldiimidazole(2.42 g, 15.0 mmol) was added to this, and the mixture was stirred withcooling in ice for 30 minutes. 40% Solution of methylamine/methanol (2mL) was added to the mixture and the mixture was stirred further for 30minutes. The reaction solution was concentrated under reduced pressure,the residue was combined with water and extracted with ethyl acetate.The extract was washed with 1 M hydrochloric acid, 1 M aqueous solutionof sodium hydroxide and water, and then concentrated under reducedpressure. The residue was crystallized from ethyl acetate-hexane toobtain the title compound (1.66 g, yield: 76%).

[1716] Melting point: 132-133° C.

[1717]¹H NMR (CDCl₃) δ3.04 (3H, d, J=4.8 Hz), 6.33 (1H, br s), 5 7.58(1H, t, J=7.8 Hz), 7.78 (1H, d, J=7.8 Hz), 8.00-8.08 (2H, m).

Reference Example 137

[1718]2,3-Dihydro-6,7-dimethoxy-2,2-dimethyl-5-(2-methyl-1-propenyl)benzofuran

[1719] 4-Hydroxy-2,3-dimethoxy-5-(2-methyl-2-propenyl)benzaldehyde wasobtained from 4-hydroxy-2,3-dimethoxybenzaldehyde by the method similarto that in Reference Example 1. This was converted to2,3-dihydro-6,7-dimethoxy-2,2-dimethyl-5-benzofurancarboxaldehyde by themethod similar to that in Reference Example 3 and converted to the titlecompound by the method similar to that in Reference Example 5. Yield:48%.

[1720] An oil.

[1721]¹H NMR (CDCl₃) δ1.50 (6H, s), 1.79 (3H, d, J=1.2 Hz), 1.89 (3H, d,J=1.2 Hz), 2.97 (2H, s), 3.73 (3H, s), 3.93 (3H, s), 6.22 (1H, s), 6.69(1H, s).

Reference Example 138

[1722]1-(1,2,3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin-2-yl)ethanone

[1723] To a solution of1,2,3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin(503 mg, 1.49 mmol) in tetrahydrofuran (5 mL), triethylamine (0.23 mL,1.64 mmol) and acetyl chloride (0.12 mL. 1.64 mmol) were added, and themixture was stirred at room temperature for 1 hour. Ice water was pouredinto the reaction mixture, which was then extracted twice with ethylacetate. The combined organic layer was washed with brine, dried overmagnesium sulfate, filtered, and concentrated under, reduced pressure.The precipitated crystals were recovered by filtration, and washed withdiethyl ether to obtain the title compound (380 mg, yield: 67%).

[1724] Melting point: 193-195° C.

[1725]¹H NMR (CDCl₃) δ1.25 (3H, s), 1.59 (3H, s), 1.61 (3H, s), 1.72(3H, s), 2.17 (1H, d, J=14.6 Hz), 2.54 (1H, d, J=14.6 Hz), 2.27 (3H, s),3.12 (2H, s), 3.88 (3H, s), 5.81 (1H, br s), 6.56 (1H, s), 7.03 (5H, m).

Reference Example 139

[1726]Phenyl(1,2,3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin-2-yl)methanone

[1727] To a solution of1,2,3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinoline(420 mg, 1.24 mmol) in tetrahydrofuran (5 mL), triethylamine (0.19 mL,1.37 mmol) and acetyl chloride (0.16 mL, 1.37 mmol) were added, and themixture was stirred at room temperature for 3 hours. The reactionmixture was poured into ice water and extracted twice with ethylacetate. The combined organic layer was washed with brine, dried overmagnesium sulfate, filtered, and concentrated under reduced pressure.The precipitated crystals were recovered by filtration and washed withhexane to obtain the title compound (415 mg, yield: 76%).

[1728] Melting point: 190-225° C.

[1729]¹H NMR (CDCl₃) δ1.42 (3H, s), 1.50 (3H, s), 1.57 (3H, s), 1.75(3H, s), 2.29 (1H, d, J=14.5 Hz), 2.60 (1H, d, J=14.5 Hz), 2.71 (2H, s),3.92 (3H, s), 5.85 (1H, s), 6.65 (1H, s), 7.07 (2H, d, J=8.6 Hz),7.23-7.27 (3H, m), 7.36 (5H, m).

Example 1

[1730]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinoline

[1731] A solution of2,3-dihydro-7-methoxy-2,2-dimethyl-5-(2-methyl-1-propenyl)benzofuran(2.09 g, 9.00 mmol) and benzonitrile (1.24 g, 12.0 mmol) in acetic acid(3 mL) was treated dropwise with conc. sulfuric acid (1.0 mL) at 10° C.,and stirred at room temperature for 40 minutes. The reaction mixture waspoured into ice water and washed with diisopropyl ether. The aqueouslayer was neutralized with conc. aqueous ammonia and extracted twicewith ethyl acetate. The combined organic layer was washed with water andbrine, dried over sodium sulfate, filtered, and concentrated underreduced pressure. The residue was subjected to a column chromatographyon a basic silica gel (hexane/ethyl acetate, 15:1 followed by 10:1), andcrystallized from hexane to obtain the title compound (1.55 g, yield:51%).

[1732] Melting point: 128-129° C.

[1733]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.30 (6H, s), 2.19 (2H, s), 2.69(2H, s), 3.92 (3H, s), 6.61 (1H, s), 7.38 (5H, s).

Example 2

[1734] 3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-(1-naphthyl)furo[2,3-h]isoquinoline

[1735] The title compound was obtained using 1-naphthonitrile by themethod similar to that in Example 1. Yield: 49%.

[1736] Melting point: 162-164° C. (ethyl acetate-hexane)

[1737]¹H NMR (CDCl₃) δ0.92 (3H, s), 1.17 (3H, s), 1.28 (3H, s), 1.29(1H, d, J=16.3 Hz), 1.46 (3H, s), 1.91 (1H, d, J=16.3 Hz), 2.78 (1H, d,J=15.6 Hz), 2.90 (1H, d, J=15.6 Hz), 3.93 (3H, s), 6.65 (1H, s),7.30-7.55 (4H, m), 7.61-7.68 (1H, m), 7.81-7.91 (2H, m).

Example 3

[1738]4-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenol

[1739] The title compound was obtained using 4-cyanophenol by the methodsimilar to that in Example 1. Yield: 48%.

[1740] Melting point: 236-239° C. (methanol-diisopropyl ether)

[1741]¹H NMR (CDCl₃) δ1.29 (6H, s), 1.30 (6H, s), 2.26 (2H, s), 2.72(2H, s), 3.92 (3H, s), 6.50 (2H, d, J=8.4 Hz), 6.60 (1H, s), 7.05 (2H,d, J=8.4 Hz).

Example 4

[1742]3,4,8,9-Tetrahydro-6-methoxy-1-(4-methoxyphenyl)-3,3,8,8-tetramethylfuro[2,3-h]isoquinoline

[1743] The title compound was obtained using 4-methoxybenzonitrile bythe method similar to that in Example 1. Yield: 49%.

[1744] Melting point: 151-152° C. (ethyl acetate-hexane)

[1745]¹H NMR (CDCl₃) δ1.23 (6H, s), 1.33 (6H, s), 2.28 (2H, s), 2.67(2H, s), 3.85 (3H, s), 3.92 (3H, s), 6.60 (1H, s), 6.91 (2H, d, J=8.8Hz), 7.34 (2H, d, J=8.8 Hz).

Example 5

[1746]3,4,8,9-Tetrahydro-6-methoxy-1-(2-methoxyphenyl)-3,3,8,8-tetramethylfuro[2,3-h]isoquinoline

[1747] The title compound was obtained using 2-methoxybenzonitrile bythe method similar to that in Example 1. Yield: 51%.

[1748] Melting point: 124-1-25° C. (ethyl acetate-hexane)

[1749]¹H NMR (CDCl₃) δ1.13 (3H, s), 1.27 (3H, s), 1.30 (3H, s), 1.42(3H, s), 2.07 (1H, d, J=16.2 Hz), 2.17 (1H, d, J=16.2 Hz), 2.61 (1H, d,J=15.6 Hz), 2.83 (1H, d, J=15.6 Hz), 3.68 (3H, s), 3.91 (3H, s), 6.57(1H, s), 6.85 (1H, d, J=8.0 Hz), 7.00 (1H, td, J=7.5, 1.0 Hz), 7.21-7.28(1H, m), 7.34 (1H, ddd, J=8.3, 7.6, 1.9 Hz).

EXAMPLE 6

[1750](3,4-Dimethoxyphenyl)-3,4,8,9-tetrahydro-1-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinoline

[1751] The title compound was obtained using 3,4-dimethoxybenzonitrileby the method similar to that in Example 1. Yield: 42%.

[1752] Melting point: 121-122° C. (diisopropyl ether-hexane)

[1753]¹H NMR (CDCl₃) δ1.24 (6H, s), 1.33 (6H, s), 2.30 (2H, s), 2.68(2H, s), 3.89 (3H, s), 3.91 (3H, s), 3.92 (3H, s), 6.61 (1H, s), 6.87(1H, d, J=8.1 Hz), 6.93 (1H, d, J=1.8 Hz), 6.97 (1H, dd, J=8.1, 1.8 Hz).

Example 7

[1754]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-(phenylmethyl)furo[2,3-h]isoquinoline

[1755] The title compound was obtained using phenylacetonitrile by themethod similar to that in Example 1. Yield: 16%.

[1756] Melting point: 77-79° C. (hexane)

[1757]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.34 (6H, s), 2.65 (2H, s), 3.06(2H, s), 3.87 (3H, s), 4.01% (2H, s), 6.54 (1H, s), 7.06-7.27 (5H, m).

Example 8

[1758]Phenyl(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)methanone

[1759] The mother liquor after filtration of the desired material inExample 7 was concentrated under reduced pressure, the residue wasallowed to stand at room temperature, and then crystallized fromdiisopropyl ether-hexane to obtain the title compound. Yield: 7.8%.

[1760] Melting point: 135-137° C.

[1761]¹H NMR (CDCl₃) δ1.33 (6H, s), 1.35 (6H, s), 2.66 (2H, s), 2.75(2H, s), 3.92 (3H, s), 6.60 (1H, s), 7.42-7.53 (2H, m), 7.56-7.67 (1H,m), 7.96-8.02 (2H, m).

Example 9

[1762]1-[1,1′-Biphenyl]-4-yl-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinoline

[1763] The title compound was obtained using 4-cyanobiphenyl by themethod similar to that in Example 1. Yield: 33%.

[1764] Amorphous.

[1765]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.33 (6H, s), 2.32 (2H, s), 2.70(2H, s), 3.93 (3H, s), 6.63 (1H, s) 7.32-7.52 (5H, m), 7.60-7.69 (4H,m).

Example 10

[1766]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-(4-methylphenyl)furo[2,3-h]isoquinoline

[1767] The title compound was obtained using 4-methylbenzonitrile by themethod similar to that in Example 1. Yield: 51%.

[1768] Melting point: 158-161° C. (ethyl acetate-hexane)

[1769]¹H NMR (CDCl₃) δ1.23 (6H, s), 1.32 (6H, s), 2.25 (2H, s), 2.39(3H, s), 2.67 (2H, s), 3.92 (3H, s), 6.60 (1H, s), 7.18 (2H, d, J=8.0Hz), 7.24-7.32 (2H, m).

Example 11

[1770]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-(2-methylphenyl)furo[2,3-h]isoquinolinehydrochloride

[1771] A free base of the title compound was obtained using2-methylbenzonitrile by the method similar to that in Example 1. Thiswas dissolved in methanol, combined with 10% solution of hydrogenchloride/methanol, and concentrated under reduced pressure to obtain thetitle compound. Yield: 54%.

[1772] Amorphous.

[1773]¹H NMR (CDCl₃) b 1.28 (3H, s), 1.30 (3H, s), 1.52 (3H, s), 1.56(31H, s), 2.01 (2H, s), 2.21 (3H, s), 2.92 (2H, s), 3.96 (3H, s), 206.68 (1H, s), 7.15-7.48 (4H, m).

Example 12

[1774]1-(4-Bromophenyl)-3,4,8.9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolinehydrochloride

[1775] The title compound was obtained using 4-bromobenzonitrile by themethod similar to that in Example 11. Yield: 40%.

[1776] Melting point: 140-145° C. (ethyl acetate-diethyl ether).

[1777]¹H NMR (DMSO-6) δ1.25 (6H, s), 1.43 (6H, s), 2.25 (2H, s), 3.15(2H, s), 3.94 (3H, s), 7.10 (1H, s), 7.59 (2H, d, J=8.6 Hz), 7.89 (2H,d, J=8.6 Hz).

Example 13

[1778]3,4,8,9-Tetrahydro-6-methoxy-1-(3-methoxyphenyl)-3,3,8,8-tetramethylfuro[2,3-h]isoquinolinehydrochloride

[1779] The title compound was obtained using 3-methoxybenzonitrile bythe method similar to that in Example 11. Yield: 49%.

[1780] Amorphous.

[1781]¹H NMR (CDCl₃) δ1.34 (6H, s), 1.48 (6H, br s), 2.30 (2H, s), 2.86(2H, br s), 3.91 (3H, s), 3.97 (3H, s), 6.67 (1H, s), 6.99-7.10 (2H, m),7.21 (1H, br s), 7.35 (1H, t, J=7.9 Hz).

Example 14

[1782]3,4,8,9-Tetrahydro-6-methoxy-1,3,3,8,8-pentamethylfuro[2,3-h]isoquinoline

[1783] A solution of2,3-dihydro-7-methoxy-2,2-dimethyl-5-(2-methyl-1-propenyl)benzofuran(697 mg, 3.00 mL) in acetonitrile (0.9 mL) was treated dropwise withconc. sulfuric acid (0.45 mL) with cooling in ice, and stirred at roomtemperature for 22 hours. The reaction mixture was poured into ice waterand washed with diisopropyl ether. The aqueous layer was neutralizedwith 2 M solution of sodium hydroxide and extracted twice with ethylacetate. The combined organic layer was washed with brine, dried overmagnesium sulfate, filtered, and concentrated under reduced pressure.The residue was subjected to a column chromatography on a basic silicagel (hexane/ethyl acetate, 5:1) and crystallized from diisopropylether-hexane to obtain the title compound (431 mg, yield: 53%).

[1784] Melting point: 112-113° C.

[1785]¹H NMR (CDCl₃) δ1.17 (6H, s), 1.53 (6H, s), 2.30 (3H, s), 2.58(2H, s), 3.27 (2H, s), 3.90 (3H, s), 6.53 (1H, s).

Example 15

[1786]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-(4-pyridinyl)furo[2,3-h]isoquinoline

[1787] A solution of 4-cyanopyridine (312 mg, 3.00 mmol) in toluene (1.5mL) was treated dropwise with conc. sulfuric acid (1.2 mL) with coolingin ice. Ice bath was removed a solution of2,3-dihydro-7-methoxy-2,2-dimethyl-5-(2-methyl-1-propenyl)benzofuran(697 mg, 3.00 mmol) in toluene (0.5 mL) was added to the mixture, andthe mixture was stirred at 80° C. for 45 minutes. The reaction mixturewas combined with ice and diluted with water and toluene. The organiclayer was separated, and the aqueous layer was neutralized with conc.aqueous ammonia and extracted twice with ethyl acetate. The combinedorganic layer was washed with water and brine, dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas subjected to a column chromatography on a basic silica gel(hexane/ethyl acetate, 3:1) and crystallized from ethyl acetate-hexaneto obtain the title compound (294 mg, yield: 29%).

[1788] Melting point: 173-175° C.

[1789]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.33 (6H, s), 2.23 (2H, s), 2.70(2H, s), 3.93 (3H, s), 6.63 (1H, s), 7.35 (2H, d, J=6.0 Hz), 8.67 (2H,d, J=6.0 Hz).

Example 16

[1790]1-(2-Fluorophenyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolinehydrochloride

[1791] A free base of the title compound was obtained using2-fluorobenzonitrile by the method similar to that in Example 15. Thiswas dissolved in ethyl acetate, combined with 0.8 M solution of hydrogenchloride/methanol, and concentrated under reduced pressure to obtain thetitle compound. Yield: 50%.

[1792] Amorphous.

[1793]¹H NMR (CDCl₃) δ1.33 (3H, s), 1.38 (3H, s), 1.61 (3H, s), 1.81(3H, s), 2.20 (1H, d, J=17.0 Hz), 2.32-2.45 (1H, m), 2.95 (1H, d, J=16.2Hz), 3.18 (1H, d, J=16.2 Hz), 4.02 (3H, s), 6.74 (1H, s), 7.15-7.28 (1H,m), 7.41 (1H, t, J=7.7 Hz), 7.59-7.76 (2H, m)).

Example 17

[1794]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-(3-pyridinyl)furo[2,3-h]isoquinoline

[1795] Conc. sulfuric acid (0.60 mL) was added to a solution of3-cyanopyridine (312 mg, 3.00 mmol) in toluene (1 mL) and acetic acid (1mL) with cooling in ice and then a solution of2,3-dihydro-7-methoxy-2,2-dimethyl-5-(2-methyl-1-propenyl)benzofuran(697 mg, 3.00 mmol) in toluene (0.5 mL) was added to the mixture. Themixture was stirred at 80° C. for 1 hour. The reaction mixture waspoured into ice water and washed with diisopropyl ether, and the aqueouslayer was neutralized with conc. aqueous ammonia and extracted twicewith ethyl acetate. The combined organic layer was washed with water andbrine, dried over sodium sulfate, filtered, and concentrated underreduced pressure. The residue was subjected to a column chromatographyon a basic silica gel (hexane/ethyl acetate, 5:1) and crystallized fromdiisopropyl ether-hexane to obtain the title compound (301 mg, yield:30%).

[1796] Melting point: 113-114° C.

[1797]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.32 (6H, s), 2.21 (2H, s), 2.71(2H, s), 3.93 (3H, s), 6.63 (1H, s), 7.34 (1H, ddd, J=7.7, 4.9, 0.8 Hz),7.75 (1H, dt, J=7.7, 1.9 Hz), 8.63 (H, d, J=0.8 Hz), 8.65 (1H, dd,J=4.9, 1.9 Hz).

Example 18

[1798]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-(2-pyridinyl)furo[2,3-h]isoquinoline

[1799] The title compound was obtained using 2-cyanopyridine by themethod similar to that in Example 17. Yield: 27%.

[1800] Melting point: 146-147° C. (diisopropyl ether-hexane)

[1801]¹H NMR (CDCl₃) δ1.28 (6H, s), 1.32 (6H, s), 2.15 (2H, s), 2.73(2H, s), 3.91 (3H, s), 6.60 (1H, s), 7.33 (1H, ddd, J=7.6, 4.9, 1.4 Hz),7.56-7.63 (1H, m), 7.99 (1H, td, J=7.6, 1.8 Hz), 8.63 (1H, ddd, J=4.9,1.8, 1.0 Hz).

Example 19

[1802]1-(4-Fluorophenyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinoline

[1803] The title compound was obtained using 4-fluorobenzonitrile by themethod similar to that in Example 17. Yield: 44%.

[1804] Melting point: 131-132° C. (hexane)

[1805]¹H NMR (CDCl₃) δ1.24 (6H, s), 1.33 (6H, s), 2.22 (2H, s), 2.68(2H, s), 3.92 (3H, s), 6.61 (1H, s), 7.08 (2H, t, J=8.8 Hz), 7.39 (2H,dd, J=8.8, 5.4 Hz).

Example 20

[1806]1-(3-Bromophenyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinoline

[1807] The title compound was obtained using 3-bromobenzonitrile by themethod similar to that in Example 17. Yield: 51%.

[1808] Melting point: 108-109° C. (hexane)

[1809]¹H NMR (CDCl₃) δ1.24 (6H, s), 1.34 (6H, s), 2.24 (2H, s), 2.68(2H, s), 3.92, (3H, s), 6.61 (1H, s), 7.25 (1H, t, J=7.6 Hz), 7.34 (1H,dt, J=7.6, 1.6 Hz), 7.52 (1H, dt, J=7.6, 1.6 Hz), 7.57 (1H, t, J=1.6Hz).

Example 21

[1810]4-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenesulfonamide

[1811] The title compound was obtained using 4-cyanobenzenesulfonamideby the method similar to that in Example 17. Yield: 55%.

[1812] Melting point: 153-168° C. (decomposition) (ethylacetate-hexane).

[1813]¹H NMR (DMSO-d₆) δ1.15 (6H, s), 1.22 (6H, s), 2.22 (2H, s), 2.65(2H, s), 3.82 (3H, s), 6.83 (1H, s), 7.54 (2H, d, J=8.4 Hz), 7.86 (2H,d, J=8.4 Hz).

Example 22

[1814]6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinoline

[1815] The title compound was obtained from7-ethoxy-2,3-dihydro-2,2-dimethyl-5-(2-methyl-1-propenyl)benzofuran andbenzonitrile by the method similar to that in Example 17. Yield: 65%.

[1816] Gummy.

[1817]¹H NMR (CDCl₃) δ1.24 (6H, s), 1.30 (6H, s), 1.46 (3H, t, J=7.0Hz), 2.17 (2H, s), 2.67 (2H, s), 4.18 (2H, q, J=7.0 Hz), 6.60 (1H, s),7.38 (5H, s).

Example 23

[1818]6-Ethoxy-3,4,8,9-tetrahydro-1-(4-methoxyphenyl)-3,3,8,8-tetramethylfuro[2,3-h]isoquinoline

[1819] The title compound was obtained using7-ethoxy-2,3-dihydro-2,2-dimethyl-5-(2-methyl-1-propenyl)benzofuran and4-methoxybenzonitrile by the method similar to that in Example 17.Yield: 55%.

[1820] Melting point: 140-142° C.(hexane).

[1821]¹H NMR (CDCl₃) δ1.22 (6H, s), 1.32 (6H, s), 1.46 (3H, t, J=7.0Hz), 2.26 (2H, s), 2.65 (2H, s), 3.84 (3H, s), 4.18 (2H, q, J=7.0 Hz),6.59 (1H, s), 6.90 (2H, d, J=8.4 Hz), 7.34 (2H, d, J=8.4 Hz).

Example 24

[1822]3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid methyl ester

[1823] Conc. sulfuric acid (1.8 mL) was added to a solution of methyl3-cyanobenzoate (2.42 g, 15.0 mmol) in toluene (15 mL) and acetic acid(8 mL) with cooling in ice and then a solution of2,3-dihydro-7-methoxy-2,2-dimethyl-5-(2-methyl-1-propenyl)benzofuran-(3.49 g, 15.0 mmol) in toluene (15 mL) was added to the mixture. Themixture was stirred at 80° C. for 1 hour. The reaction mixture wascooled with ice, combined with an aqueous solution containing sodiumacetate (6.69 g, 81.6 mmol), and then neutralized with conc. aqueousammonia and extracted twice with ethyl acetate. The combined organiclayer was washed with water and extracted with 1 M hydrochloric acid 3times. The combined aqueous layer was neutralized with conc. aqueousammonia and extracted twice with ethyl acetate. The combined organiclayer was washed with water and brine, dried over sodium sulfate,filtered, and concentrated under reduced pressure. The residue wassubjected to a column chromatography on a basic silica gel (hexane/ethylacetate 10:1) and crystallized from ethyl acetate-hexane to obtain thetitle compound (2.18 g, Yield: 37%).

[1824] Melting point: 137-138° C.

[1825]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.30 (6H, s), 2.16 (2H, s), 2.70(2H, s), 3.92 (3H, s), 3.93 (3H, s), 6.63 (1H, s), 7.48 (1H, t, J=7.8Hz), 7.62 (1H, dt, J=7.8, 1.5 Hz), 8.05-8.12 (2H, m).

Example 25

[1826]4-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,9-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid methyl ester

[1827] The title compound was obtained using methyl 4-cyanobenzoate bythe method similar to that in Example 24. Yield: 48%.

[1828] Melting point: 150-152° C. (diisopropyl ether-hexane).

[1829]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.30 (6H, s), 2.17 (2H, s), 2.70(2H, s), 3.92 (3H, s), 3.95 (3H, s), 6.62 (1H, s), 7.48 (2H, d, J=8.6Hz), 8.07 (2H, d, J=8.6 Hz).

Example 26

[1830]4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid methyl ester

[1831] The title compound was obtained-from7-ethoxy-2,3-dihydro-2,2-dimethyl-5-(2-methyl-1-propenyl)benzofuran andmethyl 4-cyanobenzoate by the method similar to that in Example 24.Yield: 43%.

[1832] Melting point: 81-85° C. (hexane).

[1833]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.30 (6H, s), 1.46 (3H, t, J=7.0Hz), 2.15 (2H, s), 2.68 (2H, s), 3.95 (3H, s), 4.18 (2H, q, J=7.0 Hz),6.61 (1H, s), 7.48 (2H, d, J=8.3 Hz), 8.07 (2H, d, J=8.3 Hz).

Example 27

[1834]4-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine

[1835] Conc. sulfuric acid (3.6 mL) was added to a suspension ofN-(4-cyanophenyl)-2,2,2-trifluoroacetamide (6.43 g, 30.0 mmol) intoluene (30 mL) and acetic acid (15 mL) with cooling in ice and then asolution of2,3-dihydro-7-methoxy-2,2-dimethyl-5-(2-methyl-1-propenyl)benzofuran(10.5 g, 45.2 mmol) in toluene (20 mL) was added to the mixture. Themixture was stirred at 80° C. for 1 hour. The reaction mixture wascooled with ice and combined with water and a small amount of methanol,and the organic layer was separated, and the aqueous layer was washedwith diisopropyl ether, neutralized with conc. aqueous ammonia, andextracted twice with ethyl acetate. The combined organic layer waswashed with water and concentrated under reduced pressure. The residuewas dissolved in ethanol (30 mL), combined with 2 M aqueous solution ofsodium hydroxide (15 mL, 30 mmol), and heated under reflux for 40minutes. The reaction mixture was concentrated under reduced pressure,and the residue was combined with water and extracted twice with ethylacetate. The combined organic layer was washed with water and brine,dried over sodium sulfate, filtered, and concentrated under reducedpressure. The residue was subjected to a column chromatography on abasic silica gel (hexane/ethyl acetate 1:1) and recrystallized fromethanol-diisopropyl ether to obtain the title compound (6.32 g, Yield:60%).

[1836] Melting point: 192-195° C.

[1837]¹H NMR (CDCl₃) δ1.21 (6H, s), 1.33 (6H, s), 2.36 (2H, s), 2.65(2H, s), 3.45-3.95 (2H, br), 3.91 (3H, s), 6.59 (1H, s), 6.68 (2H, d,J=8.5 Hz), 7.21 (2H, d, J=8.5 Hz).

Example 28

[1838]3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine

[1839] A solution of 3-aminobenzonitrile (9.48 g, 80.2 mmol) in toluene(100 mL) and acetic acid (80 mL) was cooled with ice, conc. sulfuricacid (16 mL) was added dropwise thereto, and then1-(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-2-methyl-1-propanol(22.1 g, 88.3 mmol) was added in portions thereto. The resultant mixturewas stirred at 85° C. for 1 hour. Ethanol was added dropwise to thereaction mixture, which was then stirred at the same temperature for 45minutes. The resultant mixture was cooled and then combined with waterto separate an aqueous layer, and the organic layer was extracted withwater. The combined aqueous layer was neutralized with conc. aqueousammonia and extracted twice with ethyl acetate. The combined organiclayer was washed with water, and then extracted twice with a 10% aqueoussolution of acetic acid. The combined aqueous layer was neutralized withconc. aqueous ammonia and extracted twice with ethyl acetate. Thecombined organic layer was washed twice with water and concentrated.under reduced pressure. The residue was subjected to a columnchromatography on a basic silica gel (hexane/ethyl acetate, 4:1 followedby 1:1) and crystallized from ethyl acetate-hexane to obtain the titlecompound (12.7 g, Yield: 45%).

[1840] Melting point: 131-134° C.

[1841]¹H NMR (CDCl₃) δ1.26 (6H, br s), 1.33 (6H, s), 2.33 (2H, s), 2.67(2H, s), 3.69 (2H, br s), 3.91 (3H, s), 6.59 (1H, s), 6.66-6.77 (3H, m),7.09-7.19 (1H, m).

[1842] (Alternative synthetic method)

[1843] A solution of1-(2,3-Dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-2-methyl-1-propylacetate (907 mg, 3.10 mmol) and 3-aminobenzonitrile (440 mg, 3.72 mmol)in toluene (5 mL) was heated at 85° C., a solution of conc. sulfuricacid (0.56 mL) in acetic acid (3 mL) was added dropwise thereto, and themixture was stirred at the same temperature for 1.5 hours. Ethanol wasadded dropwise to the reaction mixture, which was then stirred at thesame temperature for 1 hour. The resultant mixture was cooled with iceand combined with water to separate an aqueous layer, and the organiclayer was extracted with water. The combined aqueous layer wasneutralized with conc. aqueous ammonia and extracted twice with ethylacetate. The combined organic layer was washed with water, and thenextracted twice with a 10% aqueous solution of acetic acid. The combinedaqueous layer was neutralized with conc. aqueous ammonia and extractedtwice with ethyl acetate. The combined organic layer was washed twicewith water and concentrated under reduced pressure. The residue wascrystallized from diethyl ether-hexane to obtain the title compound (373mg, Yield: 34%).

Example 29

[1844]3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenaminedihydrochloride

[1845]3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[(2,3-h]isoquinolin-1-yl)benzenamine(351 mg, 1.00 mmol) was dissolved in ethyl acetate (10 mL), combinedwith 0.8 M hydrogen chloride/methanol (3 mL), and concentrated underreduced pressure. The residue was recrystallized fromethanol-diisopropyl ether to obtain the title compound (401 mg, Yield:95%.

[1846] Melting point: 176-180° C.

[1847]¹H NMR (DMSO-d₆) δ1.26 (6H, br s), 1.43 (6H, s), 2.23-2.38 (2H,m), 3.15 (2H, br s), 3.94 (3H, s), 6.80-7.22 (3H, m), 7.09 (1H, s),7.30-7.48 (1H, m).

Example 30

[1848]N-[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]acetamide

[1849] A solution of3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine(351 mg, 1.00 mmol) and triethylamine (0.17 mL, 1.2 mmol) intetrahydrofuran (3 mL) was treated dropwise with acetyl chloride (78 μL,1.1 mmol) with cooling in ice, and stirred at the same temperature for10 minutes. The reaction mixture was combined with water and a saturatedaqueous solution of sodium hydrogen carbonate and extracted twice withethyl acetate. The combined organic layer was washed with water andbrine, dried over sodium sulfate, filtered and concentrated underreduced pressure. The resultant crystals were washed with diisopropylether to obtain the title compound (305 mg, Yield: 78%).

[1850] Melting point: 246-247° C.

[1851]¹H NMR (DMSO-d₆) δ1.13 (6H, s), 1.21 (6H, s), 2.02 (3H, s), 2.28(2H, s), 2.62 (2H, s), 3.81 (3H, s), 6.80 (1H, s), 6.96-7.04 (1H, m),7.31 (1H, t, J=7.9 Hz), 7.55-7.67 (2H, m), 9.99 (1H, br s).

Example 31

[1852]2,2,2-Trifluoro-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]acetamide

[1853] The title compound was obtained using trifluoroacetic anhydrideby the method similar to that in Example 30. Yield: 86%.

[1854] Melting point: 241-242° C. (ethyl acetate-diisopropyl ether).

[1855]¹H NMR (DMSO-d₆) δ1.14 (6H, s), 1.21 (6H, s), 2.28 (2H, s), 2.63(2H, s), 3.82 (3H, s), 6.82 (1H, s), 7.17-7.25 (1H, m), 7.45 (1H, t,J=7.7 Hz), 7.65-7.78 (2H, m), 11.31 (1H, br s).

Example 32

[1856]N-[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]methanesulfonamide

[1857] The title compound was obtained from3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamineand methanesulfonyl chloride by the method similar to that in Example30. Yield: 58%.

[1858] Melting point: 245-247° C. (ethanol).

[1859]¹H NMR (CDCl₃) δ1.27 (6H, br s), 1.33 (6H, s), 2.24 (2H, s), 2.71(2H, s), 2.88 (3H, s), 3.92 (3H, s), 6.61 (1H, s), 7.15 (1H, dt, J=6.3,1.9 Hz), 7.19-7.23 (1H, m), 7.26-7.40 (2H, m).

Example 33

[1860]2,2,2-Trifluoro-N-[4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]acetamide

[1861] The title compound was obtained from4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamineand trifluoroacetic anhydride by the method similar to that in Example30. Yield: 89%.

[1862] Melting point: 117-123° C. (ethyl acetate-diisopropyl ether).

[1863]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.32 (6H, s), 2.23 (2H, s), 2.69(2H, s), 3.92 (3H, s), 6.62 (1H, s), 7.39 (2H, d, J=8.6 Hz), 7.56 (2H,d, J=8.6 Hz), 8.30-8.60 (1H, br).

Example 34

[1864]N-[4-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]acetamide

[1865] The title compound was obtained from4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamineand acetyl chloride by the method similar to that in Example 30. Yield:90%.

[1866] Melting point: 119-123° C. (ethyl acetate-diisopropyl ether).

[1867]¹H NMR (CDCl₃) δ1.23 (6H, s), 1.32 (6H, s), 2.19 (3H, s), 2.27(2H, s), 2.68 (2H, s), 3.92 (3H, s), 6.61 (1H, s), 7.35 (2H, d, J=8.5Hz), 7.44 (1H, br s), 7.54 (2H, d, J=8.5 Hz).

Example 35

[1868]3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenylcarbamicacid phenyl ester

[1869] The title compound was obtained using phenyl chloroformate by themethod similar to that in Example 30. Yield: 88%.

[1870] Melting point: 155-164° C. (ethyl acetate-hexane).

[1871]¹H NMR (CDCl₃) δ1.26 (6H, br s), 1.32 (6H, s), 2.30 (2H, s), 2.69(2H, br s), 3.92 (3H, s), 6.60 (1H, s), 7.05-7.11 (1H, m), 7.13-7.57(9H, m).

Example 36

[1872]N-[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3.8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]benzamide

[1873] The title compound was obtained from benzoyl chloride by themethod similar to that in Example 30. Yield: 93%.

[1874] Melting point: 124-130, 174-176° C. (ethyl acetate-hexane).

[1875]¹H NMR (CDCl₃) δ1.21 (6H, br s), 1.33 (6H, s), 2.35 (2H, s), 2.65(2H, s), 3.92 (3H, s), 6.60 (1H, s), 7.12 (1H, dt, J=7.8, 1.3 Hz), 7.38(1H, t, J=7.8 Hz), 7.41-7.60 (4H, m), 7.82-7.98 (3H, m), 8.26 (1H, brs).

Example 37

[1876]2-Chloro-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]acetamide

[1877] The title compound was obtained using chloroacetyl chloride bythe method similar to that in Example 30. Yield: 86%.

[1878] Melting point: 205-207° C. (ethyl acetate-diethyl ether).

[1879]¹H NMR (CDCl₃) δ1.24 (6H, br s), 1.32 (6H, s), 2.28 (2H, s), 2.68(2H, s), 3.92. (3H, s), 4.18 (2H, s), 6.61 (1H, s), 7.12-7.19 (1H, m),7.37 (1H, t, J=7.9 Hz), 7.46 (1H, t, J=1.7 Hz), 7.73-7.80 (1H, m), 8.37(1H, br s).

Example 38

[1880]2-(Methylthio)-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]acetamide

[1881] A suspension of2-chloro-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]acetamide(2.20 g, 5.15 mmol) in N,N-dimethylformamide (15 mL) was treateddropwise with a 15% aqueous solution of methylmercaptan sodium salt (3.1g, 6.6 mmol) slowly, and stirred at 60° C. for 40 minutes. The reactionmixture was combined with water, and extracted twice with ethyl acetate.The combined organic layer was washed twice with water, and concentratedunder reduced pressure. The residue was crystallized from ethylacetate-diethyl ether to obtain the title compound (1.92 g, yield: 85%).

[1882] Melting point: 139-141° C.

[1883]¹H NMR (CDCl₃) δ1.25 (6H, br s), 1.32 (6H, s), 2.19 (3H, s), 2.29(2H, s), 2.69 (2H, s), 3.34 (2H, s), 3.92 (3H, s), 6.61 (1H, s), 7.12(1H, dt, J=7.9, 1.1 Hz), 7.36 (1H, t, J=7.9 Hz), 7.44 (1H, t, J=2.0 Hz),7.84 (1H, ddd, J=7.9, 2.0, 1.1 Hz), 8.81 (1H, br s).

Example 39

[1884]2-(Methylsulfinyl)-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]acetamide

[1885] A suspension of2-(methylthio)-N-[3-(3,4,8-9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]acetamide(1.37 g, 3.12 mmol) in methanol (15 mL) was treated dropwise with asolution of sodium metaperiodate (1.67 g, 7.81 mmol) in water(10 mL)slowly, and stirred at room temperature for 15 minutes. The reactionmixture was combined with water and as saturated aqueous solution ofsodium hydrogen carbonate, and extracted twice with ethyl acetate. Thecombined organic layer was washed twice with water, and concentratedunder reduced pressure. The residue was subjected to a columnchromatography on a basic silica gel (hexane/ethyl acetate, 1:1 followedby ethyl acetate/methanol 10:1) and crystallized from ethylacetate-diethyl ether to obtain the title compound (1.02 g, Yield: 72%).

[1886] Melting point: 198-201° C.

[1887]¹H NMR (CDCl₃) δ1.23 (6H, br s), 1.32 (6H, s), 2.28 (2H, s), 2.68(2H, s), 2.76 (3H, s), 3.38 (1H, d, J=14.6 Hz), 3.87 (1H, d, J=14.6 Hz),3.92 (3H, s), 6.60 (1H, s), 7.12 (1H, dt, J=7.8, 1.3 Hz), 7.33 (1H, t,J=7.8 Hz), 7.48-7.53 (1H, m), 7.66-7.75 (1H, m), 9.21 (1H, br s).

Example 40

[1888]2-(Methylsulfonyl)-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]acetamide

[1889] A suspension of2-(methylthio)-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]acetamide(877 mg, 2.00 mmol) in methanol (15 mL) was treated dropwise with asolution of sodium metaperiodate (1.43 g, 6.69 mmol) in water (10 mL)and heated under reflux for 24 hours. The reaction mixture was combinedwith water and a saturated aqueous solution of sodium hydrogencarbonate, and extracted twice with chloroform. The combined organiclayer was washed with water and brine, dried over sodium sulfate,filtered and concentrated under reduced pressure. The residue wassubjected to a column chromatography on a basic silica gel (hexane/ethylacetate, 1:1, 1:3 followed by 1:20) and crystals were washed with amixture of ethyl acetate and diethyl ether to obtain the title compound(239 mg, Yield: 25%).

[1890] Melting point: 135-140° C.

[1891]¹H NMR (DMSO-d₆) δ1.14 (6H, s), 1.22 (6H, s), 2.29 (2H, s), 2.63(2H, s), 3.16 (3H, s), 3.81 (3H, s), 4.27 (2H, s), 6.81 (1H, s), 7.10(1H, d, J=7.7 Hz), 7.38 (1H, t, J=7.7 Hz), 7.59 (1H, d, J=7.7 Hz), 7.66(1H, s), 10.54 (1H, br s).

Example 41

[1892]3-(Methylthio)-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]propanamide

[1893] The title compound was obtained using 3-methylthiopropionylchloride by the method similar to that in Example 30. Yield: 99%.

[1894] Melting point: 195-197° C. (ethyl acetate-diethyl ether).

[1895]¹H NMR (CDCl₃) δ1.25 (6H, br s), 1.32 (6H, s), 2.16 (3H, s), 2.29(2H, s), 2.61 (2H, t, J=7.0 Hz), 2.68 (2H, br s), 2.86 (2H, t, J=7.0Hz), 3.92 (3H, s), 6.60 (1H, s), 7.07 (1H, d, J=7.4 Hz), 7.25-7.37 (1H,m), 7.42 (1H, s), 7.72 (1H, d, J=7.6 Hz), 7.97 (1H, br s).

Example 42

[1896]3-(Methylsulfinyl)-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]propanamide

[1897] The title compound was obtained from3-(methylthio)-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]propanamideby the method similar to that in Example 39. Yield: 83%.

[1898] Melting point: 178-179° C. (ethyl acetate-diethyl ether).

[1899]¹H NMR (CDCl₃) δ1.23 (6H, br s), 1.31 (6H, s), 2.25 (2H, s), 2.65(3H, s), 2.67 (2H, br s), 2.87-3.03 (3H, m), 3.15-3.34 (1H, m), 3.92(3H, s), 6.59 (1H, s), 7.03 (1H, d, J=7.2 Hz), 7.21-7.32 (1H, m), 7.43(1H, s), 7.72 (1H, d, J=8.0 Hz), 9.27 (1H, br s).

Example 43

[1900]N-[4-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]methanesulfonamide

[1901] A solution of4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine(1.05 g. 3.00 mmol) in pyridine (7 mL) was treated dropwise withmethanesulfonyl chloride (0.50 mL, 6.5 mmol) with cooling in ice, andstirred at the same temperature for 1 hour and at room temperature for80 minutes. The reaction mixture was combined with water and a saturatedaqueous solution of sodium hydrogen carbonate and extracted twice withethyl acetate. The combined organic layer was washed with water andbrine, dried over sodium sulfate, filtered, and concentrated underreduced pressure. The residue was suspended in toluene, concentratedunder reduced pressure, and then recrystallized from ethanol-diethylether to obtain the title compound (500 mg, Yield: 39%).

[1902] Melting point: 235-237° C.

[1903]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.33 (6H, s), 2.24 (2H, s), 2.69(2H, s), 3.00 (3H, s), 3.92 (3H, s), 6.61 (1H, s), 7.21 (2H, d, J=8.8Hz), 7.38 (2H, d, J=8.8 Hz).

Example 44

[1904]N-(Methylsulfonyl)-N-[4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]methanesulfonamide

[1905] A suspension ofN-[4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]methanesulfonamide(564 mg, 1.32 mmol) and triethylamine (0.55 mL, 3.9 mmol) intetrahydrofuran (6 mL) was treated dropwise with methanesulfonylchloride (0.20 mL, 2.6 mmol), and stirred at 70° C. for 30 minutes. Thereaction mixture was combined with water and a saturated aqueoussolution of sodium hydrogen carbonate, and extracted twice with ethylacetate. The combined organic layer was washed twice with water, andconcentrated under reduced pressure. The residue was subjected to acolumn chromatography on a basic silica gel (hexane/ethyl acetate, 3:1followed by 1:1) and recrystallized from ethyl acetate-ethyl ether toobtain the title compound (454 mg, Yield: 68%).

[1906] Melting point: 223-225° C.

[1907]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.30 (6H, s), 2.14 (2H, s), 2.70(2H, s), 3.41 (6H, s), 3.92 (3H, s), 6.62 (1H, s), 7.39 (2H, d, J=8.6Hz), 7.50 (2H, d, J=8.6 Hz).

Example 45

[1908]N-(Methylsulfonyl)-N-[3-(3.4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]methanesulfonamide

[1909] The title compound was obtained from3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamineby the method similar to that in Example 44. Yield: 63%.

[1910] Melting point: 192-195° C. (acetone-hexane).

[1911]¹H NMR (CDCl₃) δ1.25 (6H, br s), 1.32 (6H, s), 2.05-2.55 (2H, m),2.70 (2H, br s), 3.41 (6H, s), 3.92 (3H, s), 6.61 (1H, s), 7.29 (1H, t,J=1.7 Hz), 7.38 (1H, dt, J=7.5, 1.7 Hz), 7.53 (1H, t, J=7.5 Hz), 7.61(1H, dt, J=7.5, 1.7 Hz).

Example46

[1912]N-[4-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-3-pyridinecarboxamide

[1913] Nicotinoyl chloride hydrochloride (712 mg, 4.00 mmol) was addedto a solution of4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine(701 mg, 2.00 mmol) and 4-dimethylaminopyridine (611 mg, 5.00 mol) inN,N-dimethylformamide (10 mL) and the mixture was stirred at roomtemperature for 20 minutes. The reaction mixture was combined with waterand a saturated aqueous solution of sodium hydrogen carbonate, andextracted twice with ethyl acetate. The combined organic layer waswashed twice with water, and concentrated under reduced pressure. Theresidue was subjected to a column chromatography on a basic silica gel(hexane/ethyl acetate, 2:1 followed by 1:3) and crystallized from ethylacetate-hexane to obtain the title compound (181 mg, Yield: 20%).

[1914] Melting point: 130-137° C.

[1915]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.33 (6H, s), 2.31 (2H, s), 2.69(2H, s), 3.93 (3H, s), 6.62 (1H, s), 7.38-7.51 (1H, m), 7.42 (2H, d,J=8.6 Hz), 7.70 (2H, d, J=8.6 Hz), 8.21 (1H, br s), 8.25 (1H, dt, J=8.0,2.0 Hz), 8.79 (1H, dd, J=4.8, 1.4 Hz), 9.14 (1H, dd, J=2.6, 0.8 Hz).

Example 47

[1916]N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-4-pyridinecarboxamide

[1917] The title compound was obtained from3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamineand isonicotinoyl chloride hydrochloride by the method similar to thatin Example 46. Yield: 83%.

[1918] Melting point: 233-236° C. (ethyl acetate-diethyl ether).

[1919]¹H NMR (CDCl₃) δ1.17 (6H, br s), 1.33 (6H, s), 2.33 (2H, s), 2.60(2H, s), 3.92 (3H, s), 6.59.(1H, s), 7.13 (1H, d, J=7.7 Hz), 7.36 (1H,t, J=7.7 Hz), 7.51-7.56 (1H, m), 7.71 (2H, d, J=6.1 Hz), 7.86-7.93 (1H,m), 8.76 (2H, d, J=6.1 Hz), 8.98 (1H, br s).

Example 48

[1920]N-[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2-pyridinecarboxamide

[1921] The title compound was obtained from3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamineand picolinoyl chloride hydrochloride by the method similar to that inExample 46. Yield: 86%.

[1922] Melting point: 179-183° C. (ethyl acetate-hexane).

[1923]¹H NMR (CDCl₃) δ1.26 (6H, br s), 1.32 (6H, s), 2.32 (2H, s), 2.70(2H, s), 3.92 (3H, s), 6.61 (1H, s), 7.15 (1H, d, J=7.8 Hz), 7.41 (1H,t, J=8.1 Hz), 7.44 (1H, m), 7.71 (1H, t, J=1.8 Hz), 7.86-7.96 (1H, m),7.97-8.04 (1H, m), 8.26-8.32 (1H, m), 8.60 (1H, dt, J=4.7, 0.7 Hz),10.12 (1H, br s).

Example 49

[1924]N-[4-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-4-pyridinecarboxamide

[1925] The title compound was obtained using isonicotinoyl chloridehydrochloride by. the method similar to that in Example 46. Yield: 90%.

[1926] Melting point: 159-163° C. (ethyl acetate-diethyl ether).

[1927]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.33 (6H, s), 2.30 (2H, s), 2.69(2H, s), 3.93 (3H, s), 6.62 (1H, s), 7.42 (2H, d, J=8.4 Hz), 7.69 (2H,d, J=8.4 Hz), 7.75 (2H, d, J=6.2 Hz), 8.21 (1H, br s), 8.81 (2H, d,J=6.2 Hz).

Example 50

[1928]N-[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-3-pyridinecarboxamide

[1929] A solution of sodium carbonate (466 mg, 4.40 mmol) in water (4mL) was added to a solution of3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine(701 mg, 2.00 mmol) in tetrahydrofuran (4 mL). Nicotinoyl chloridehydrochloride (392 mg, 2.20 mmol) was added to the mixture with coolingin ice, and the mixture was stirred at room temperature for 20 minutes.Furthermore a solution of sodium carbonate (466 mg, 4.40 mmol) in water(2mL) and nicotinoyl chloride hydrochloride (392 mg, 2.20 mmol) wereadded to the mixture and the mixture was stirred at room temperature for15 minutes. The reaction mixture was combined with water and extractedtwice with ethyl acetate. The combined organic layer was washed withwater and brine, dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The residue was crystallized from ethylacetate-hexane to obtain the title compound (783 mg, Yield:86%).

[1930] Melting point: 213-219° C.

[1931]¹H NMR (CDCl₃) δ1.16 (6H, br s), 1.33 (6H, s), 2.34 (2H, s), 2.60(2H, br s), 3.92 (3H, s), 6.58 (1H, s), 7.09-7.18 (1H, m), 7.30-7.46(2H, m), 7.52-7.58 (1H, m), 7.88-7.97 (1H, m), 8.19 (1H, dt, J=7.9, 1.9Hz), 8.75 (1H, dd, J=5.0, 1.6 Hz), 8.88-9.10 (1H, m), 9.08 (1H, d, J=1.6Hz).

Example 51

[1932]N-(3-Pyridinecarbonyl)-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]glycinemethyl ester

[1933] Sodium hydride.(66% suspension in oil) (0.22 g, 6.1 mmol) wasadded to a solution ofN-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-3-pyridinecarboxamide(1.37 g, 3.01 mmol) in N,N-dimethylformamide (10 mL) with cooling inice, and the mixture was stirred at room temperature for 10 minutes.Methyl bromoacetate (0.62 mL, 6.5 mmol) was added to the mixture and themixture was stirred at room temperature for 30 minutes. The reactionmixture was poured into a saturated aqueous solution of ammoniumchloride, and extracted twice with ethyl acetate. The combined organiclayer was washed with water and brine, dried over sodium sulfate,filtered, and concentrated under reduced pressure. The residue wassubjected to a column chromatography on a basic silica gel (hexane/ethylacetate 2:1, 1:1 followed by 1:2) to obtain the title compound (1.12 g,Yield: 71%).

[1934] Amorphous.

[1935]¹H NMR (CDCl₃) δ1.23 (6H, br s), 1.36 (6H, s), 2.09 (2H, br s),2.67 (2H, br s), 3.79 (3H, s), 3.92 (3H, s), 4.66 (2H, br s), 6.00 (1H,s), 7.10-7.30 (4H, m), 7.36 (1H, br s), 7.82 (1H, dt, J=8.0, 2.0 Hz),8.49 (1H, dd, J=4.9, 1.7 Hz), 8.55 (1H, d, J=2.0 Hz).

Example 52

[1936]N-Methyl-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-3-pyridinecarboxamide

[1937] The title compound was obtained using iodomethane by the methodsimilar to that in Example 51. Yield: 69%.

[1938] Melting point: 151-153° C. (ethyl acetate-hexane).

[1939]¹H NMR (CDCl₃) δ1.23 (6H, br s), 1.36 (6H, s), 2.08 (2H, br s),2.67 (2H, br s), 3.54 (3H, s), 3.92 (3H, s), 6.61 (1H, s), 6.99-7.07(1H, m), 7.13-7.37 (4H, m), 7.76 (1H, dt, J=7.9, 1.8 Hz), 8.47 (1H, dd,J=4.9, 1.8 Hz), 8.50-8.54 (1H, m).

Example 53

[1940]N-(3-Pyridinylmethyl)-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]benzamide

[1941] The title compound was obtained fromN-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]benzamideand 3-chloromethylpyridine by the method similar to that in Example 51.Yield: 95%.

[1942] Melting point: 98-104° C. (ethyl acetate-hexane).

[1943]¹H NMR (CDCl₃) δ1.22 (6H, br s), 1.30 (6H, s), 2.02 (2H, s), 2.65(2H, s), 3.91 (3H, s), 5.17 (2H, br s), 6.60 (1H, s), 6.81 (1H, dt,J=6.4, 2.5 Hz), 7.05-7.32 (7H, m), 7.37-7.45 (2H, m), 7.77 (1H, dt,J=7.9, 1.9 Hz), 8.52 (1H, dd, J=4.7, 1.9 Hz), 8.59 (1H, d, J=1.8 Hz).

Example 54

[1944]N-(3-pyridinylmethyl)-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenaminetrihydrochloride

[1945] 5 M aqueous solution of sodium hydroxide (1.9mL, 9.5 mmol) wasadded to a solution ofN-(3-pyridinylmethyl)-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]benzamide(1.05 g, 1.92 mmol) in methanol (5 mL) and the mixture was heated underreflux for 8 hours. The reaction mixture was combined with water, andextracted twice with ethyl acetate. The combined organic layer waswashed with water and brine, dried over sodium sulfate, filtered, andconcentrated under reduced pressure to obtain a free base of the titlecompound. This was dissolved in methanol (5 mL), combined with 0.8 Msolution of hydrogen chloride/methanol (10 mL), and concentrated underreduced pressure. The residue was crystallized from ethanol-diethylether to obtain the title compound (826 mg, Yield: 78%).

[1946] Melting point: 156-159° C.

[1947]¹H NMR (DMSO-d₆) δ1.23 (6H, s), 1.43 (6H, s), 2.25 (2H, s), 3.14(2H, s), 3.93 (3H, s), 4.62 (2H, s), 6.71-6.79 (1H, m), 6.84 (1H, s),6.98 (1H, dd, J=8.4, 1.4 Hz), 7.09 (1H, s), 7.33 (1H, t, J=7.9 Hz), 8.07(1H, dd, J=8.0, 5.5 Hz), 8.60 (1H, d, J=8.4 Hz), 8.86 (1H, d, J=5.5 Hz),8.91 (1H, s).

Example 55

[1948]N-(Methylsulfonyl)-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]glycinemethyl ester

[1949] The title compound was synthesized fromN-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]methanesulfonamideby the method similar to that in Example 51. Yield: 98%.

[1950] Amorphous.

[1951]¹H NMR (CDCl₃) δ1.25 (6H, br s), 1.32 (6H, s), 2.23 (2H, br s),2.70 (2H, br s), 3.16 (3H, s), 3.75 (3H, s), 3.92 (3H, s), 4.51 (2H, brs), 6.61 (1H, s), 7.39-7.58 (4H, m).

Example 56

[1952]N-[(Dimethylamino)methylene]-3-[(methylsulfonyl)[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]amino]propanesulfonamide

[1953] N,N-dimethylformamide dimethylacetal (0.73 mL, 5.5 mmol) wasadded to a suspension of 3-chloro-1-propanesulfonamide (788 mg, 5.00mmol) in toluene (10 mL), and the mixture was stirred at 60° C. for 30minutes. The reaction mixture was concentrated under reduced pressure toobtain the mixture (1.15 g) containing3-chloro-N-[(dimethylamino)methylene]-1-propanesulfonamide.

[1954] Sodium hydride (66% suspension in oil).(77 mg, 2.1 mmol) wasadded to a solution ofN-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]methanesulfonamide(757 mg, 1.77 mmol) and sodium iodide (69 mg, 0.46 mmol) inN,N-dimethylformamide (4 mL) and the mixture was stirred at roomtemperature for 15 minutes. A solution of the mixture (528 mg)containing 3-chloro-N-[(dimethylamino)methylene]-1-propansulfonamide inN,N-dimethylformamide (0.5 mL) was added to the reaction mixture, andthe reaction mixture was stirred at 60° C. for 19 hours. The reactionmixture was combined with water, and extracted with ethyl acetate 3times. The combined organic layer was washed with water and brine, driedover sodium sulfate, filtered, and concentrated under reduced pressure.The residue was subjected to a column chromatography on a silica gel(ethyl acetate followed by ethyl acetate/methanol 1:1) to obtain thetitle compound (879 mg, Yield: 82%).

[1955] Amorphous.

[1956]¹H NMR (CDCl₃) δ1.25 (6H, br s), 1.32 (6H, s), 1.91-2.08 (2H, m),2.23 (2H, s), 2.70 (2H, s), 2.92 (3H, s), 3.02-3.13 (2H, m), 3.03 (3H,s), 3.13 (3H, s), 3.82 (2H, t, J=6.9 Hz), 3.92 (3H, s), 6.61 (1H, s),7.27-7.52 (4H, m), 8.00 (1H, s).

Example 57

[1957]3-[(Methylsulfonyl)[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]amino]propanesulfonamidehydrochloride

[1958]N-[(dimethylamino)methylene]-3-[(methylsulfonyl)[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]amino]propanesulfonamide(625 mg, 1.03 mmol) was dissolved in 2 M hydrochloric acid (2 mL), andheated under reflux for 30 minutes. The reaction mixture was neutralizedwith sodium hydrogen carbonate, diluted with water, and extracted twicewith ethyl acetate. The combined organic layer was washed with water andbrine, dried over sodium sulfate, filtered, and concentrated underreduced pressure to obtain a free base of the title compound. This wasdissolved in methanol (2 mL), and concentrated under reduced pressure toobtain the title compound (582 mg, Yield: 96%).

[1959] Amorphous.

[1960]¹H NMR (DMSO-d₆) δ1.20 (3H, s), 1.23 (3H, s), 1.45 (3H, s), 1.48(3H, s), 1.70-1.90 (2H, m), 2.05 (1H, d, J=16.6 Hz), 2.31 (1H, d, J=16.6Hz), 2.95-3.20 (2H, m), 3.11 (3H, s), 3.18 (2H, br s), 3.81 (2H, t,J=6.1 Hz), 3.94 (3H, s), 6.84 (2H, br s), 7.10 (1H, s), 7.50-7.82 (4H,m), 12.80-12.95 (1H, br).

Example 58

[1961]2-[(Methylsulfonyl)[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]amino]acetamide

[1962] Potassium tert-butoxide (90%) (225 mg, 1.8 mmol) was added to asolution ofN-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]methanesulfonamide(643 mg, 1.50 mmol) in tetrahydrofuran (5 mL) and the mixture wasstirred at room temperature for 5 minutes. 2-Bromoacetamide (290 mg,2.10 mmol) was added to the resultant mixture and the mixture wasstirred at 60° C. for 1 hour. Potassium tert-butoxide (90%) (56 mg, 0.45mmol) and 2-bromoacetamide (62 mg, 0.45 mmol) were added to the mixtureand the mixture was stirred at 60° C. for 30 minutes. The reactionmixture was cooled with ice, combined with water, and extracted twicewith ethyl acetate. The combined organic layer was washed with water andbrine, dried over sodium sulfate, filtered, and concentrated underreduced pressure. The residue was subjected to a column chromatographyon a basic silica gel (ethyl acetate), and crystallized from ethylacetate-diethyl ether to obtain the title compound (469 mg. Yield: 64%).

[1963] Melting point: 190-191° C.

[1964]¹H NMR (CDCl₃) δ1.25 (6H, br s), 1.32 (6H, s), 2.26 (2H, br s),2.70 (2H, s), 3.09 (3H, s), 3.92 (3H, s), 4.32 (2H, s), 5.36-5.58 (1H,br), 6.08-6.28 (1H, br), 6.61 (1H, s), 7.38-7.56 (4H, m).

Example 59

[1965]2-[[[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]amino]carbonyl]benzoicacid

[1966] A solution of phthalic anhydride (222 mg, 1.50 mmol) intetrahydrofuran (2 mL) was added to a solution of3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine(526 mg, 1.50 mmol) in tetrahydrofuran (3 mL), and stirred at roomtemperature for 15 minutes. The reaction mixture was combined withdiisopropyl ether, and crystals were recovered by filtration andrecrystallized from ethanol-ethyl acetate to obtain the titlecompound(630 mg, Yield: 84%).

[1967] Melting point: 194-197° C.

[1968]¹H NMR (DMSO-d₆) δ1.15 (6H, s), 1.24 (6H, s), 2.35 (2H, br s),2.66 (2H, br s), 3.82 (3H, s), 6.82 (1H, s), 7.08 (1H, d, J=7.6 Hz),7.37 (1H, t, J=7.7 Hz), 7.50-7.65 (3H, m), 7.67 (1H, d, J=7.8 Hz), 7.81(1H, s), 7.83-7.90 (1H, m), 10.46 (1H, br s).

Example 60

[1969]2-[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-1H-isoindole-1,3(2H)-dione

[1970] A mixture of3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine(491 mg, 1.40 mmol) and phthalic anhydride (208 mg, 1.40 mmol) in xylene(3 mL) was heated under reflux for 10 minutes. The reaction mixture wasdissolved in ethyl acetate, washed with water, a saturatedaqueous.solution of sodium hydrogen carbonate and brine, dried oversodium sulfate, filtered, and concentrated under reduced pressure. Theresidue was subjected to a column chromatography on a silica gel(hexane/ethyl acetate 2:1 followed by 1:2), and crystallized from ethylacetate-hexane to obtain the title compound (439 mg, Yield: 65%).

[1971] Melting point: 162-168° C.

[1972]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.37 (6H, s), 2.10-2.80 (2H, br),2.68 (2H, s), 3.92 (3H, s), 6.60 (1H, s), 7.44-7.61 (4H, m), 7.73-7.84(2H, m), 7.88-7.99 (2H, m).

Example 61

[1973]6-[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione

[1974] A mixture of3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine(701 mg, 2.00 mmol) and 2,3-pyridinedicarboxylic anhydride (298 mg, 2.00mmol) in tetrahydrofuran (4 mL) was stirred at room temperature for 15minutes. The reaction mixture was combined with diethyl ether, andcrystals were recovered by filtration. This was suspended in aceticanhydride (4 mL), and stirred at 100° C. for 1 hour. The reactionmixture was concentrated under reduced pressure, and the residue wascombined with ethyl acetate and a saturated aqueous solution of sodiumhydrogen carbonate, stirred vigorously, and diluted with water, and thenthe organic layer was separated, and the aqueous layer was extractedwith ethyl acetate. The combined organic layer was washed with water andbrine, dried over sodium sulfate, filtered, and concentrated underreduced pressure. The residue was subjected to a column chromatographyon a silica gel (hexane/ethyl acetate 1:3) to obtain the title compound(724 mg, 75%).

[1975] Amorphous.

[1976]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.38 (6H, s), 2.25-2.60 (2H, br),2.69 (2H, s), 3.93 (3H, s), 6.61 (1H, s), 7.46-7.60 (4H, m), 7.70 (1H,dd, J=7.7, 4.8 Hz), 8.26 (1H, dd, J=7.7, 1.5 Hz.), 9.05 (1H, dd, J=4.8,1.5 Hz).

Example 62

[1977]2-[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione

[1978] The title compound was obtained using 3,4-pyridinedicarboxylicanhydride by the method similar to that in Example 61. Yield: 77%.

[1979] Melting point: 123-129° C. (decomposition) (ethylacetate-hexane).

[1980]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.38 (6H, s), 2.15-2.70 (2H, br),2.69 (2H, s), 3.92 (3H, s), 6.61 (1H, s), 7.42-7.63 (4H, m), 7.84 (1H,dd, J=4.8, 0.8 Hz), 9.14 (1H, d, J=4.8 Hz), 9.24 (1H, d, J=0.8 Hz).

Example 63

[1981]4-[[[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]amino]carbonyl]-1-piperidinecarboxylicacid 1,1-dimethylethyl ester

[1982] 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.00g, 5.22 mmol) was added to a solution ofN-(tert-butoxycarbonyl)isonipecotic acid (1.01 g, 4.41 mmol) and1-hydroxy-1H-benzotriazole monohydrate (678 mg, 4.43 mmol) inN,N-dimethylformamide (15 mL) and the mixture was stirred at roomtemperature for 1 hour.3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2.3-h]isoquinolin-1-yl)benzenamine(1.41 g, 4.02 mmol) was added to the resultant mixture and the mixturewas stirred at room temperature for 4 hours. The reaction mixture wascombined with a saturated sodium hydrogen carbonate and water, andextracted twice with ethyl acetate. The combined organic layer waswashed with water and brine, dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was subjected to acolumn chromatography on a silica gel-(hexane/ethyl acetate 3:1, 1:1followed by 1:2). This was dissolved in ethyl acetate and washed with a2% aqueous solution of acetic acid (twice), water and a saturatedaqueous solution of sodium hydrogen carbonate, dried over sodiumsulfate, filtered, and concentrated under reduced pressure to obtain thetitle compound (1.83 g, Yield; 81%).

[1983] Amorphous.

[1984]¹H NMR (CDCl₃) δ1.23 (6H, br s), 1.32 (6H, s), 1.46 (9H, s),1.60-1.92 (4H, m), 2.22-2.42 (1H, m), 2.30 (2H, s), 2.62-2.85 (2H, m),2.68 (2H, br s), 3.92 (3H, s), 4.06-4.29 (2H, m), 6.60 (1H, s), 7.05(1H, d, J=7.6 Hz), 7.25-7.36 (1H, m), 7.48 (1H, s), 7.63-7.85 (2H, m).

Example 64

[1985]N-[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-4-piperidinecarboxamidedihydrochloride

[1986] 4 M solution of hydrogen chloride/ethyl acetate (2.0 ML) wasadded to a solution of4-[[[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]amino]carbonyl]-1-piperidinecarboxylicacid 1,1-dimethylethyl ester (1.44 g, 2.56 mmol) in ethyl acetate (15mL) and the mixture was stirred at room temperature for 1.5 hours, andthen at 60° C. for 1 hour. Ethanol (3 mL) was added to the resultantmixture and the mixture was stirred at 60° C. for 1 hour. The reactionmixture was cooled, and the crystals were recovered by filtration toobtain the title compound (774 mg, 57%).

[1987] Melting point: 217-224° C.

[1988]¹H NMR (DMSO-d₆) δ1.23 (6H, s), 1.44 (6H, br s), 1.68-2.07 (4H,m), 2.10-2.50 (2H, m), 2.65-3.40 (7H, m), 3.95 (3H, s), 7.11 (1H, s),7.31 (1H, d, J=8.2 Hz), 7.59 (1H, t, J=8.2 Hz.), 7.86 (1H, d, J=8.2 Hz),8.03 (1H, s), 8.70-9.35 (2H, m), 10.78-10.90 (1H, m), 12.50-12.80 (1H,br).

Example 65

[1989]N-[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-4-pyridineacetamide

[1990] Triethylamine (0.77 mL, 5.5 mol.) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (537 mg,2.80 mmol) were added to a solution of3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine(701 mg, 2.00 mmol), 4-pyridineacetic acid hydrochloride (417 mg, 2.40mmol) and 1-hydroxy-1H-benzotriazole monohydrate (368 mg, 2.40 mmol) inN,N-dimethylformamide (10 mL) and the mixture was stirred at roomtemperature for 1 hour. The mixture was combined with water and asaturated aqueous solution of sodium hydrogen carbonate, and extractedtwice with a mixture of ethyl acetate/methanol (5:1). The combinedorganic layer was washed twice with water, and concentrated underreduced pressure. The residue was recrystallized from ethanol-diethylether to obtain the title compound (523 mg, yield: 56%).

[1991] Melting point: 124-128° C.

[1992]¹H NMR (CDCl₃) δ1.23 (6H, br s), 1.30 (6H, s), 2.27 (2H, s), 2.67(2H, br s), 3.67 (2H, s), 3.92 (3H, s), 6.60 (1H, s), 7.03-7.10 (1H, m),7.24-7.40 (4H, m), 7.67-7.74 (1H, m), 7.91 (1H, br s), 8.60 (2H, d,J=5.8 Hz).

Example 66

[1993]N-[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-3-pyridineacetamide.

[1994] The title compound was obtained using 3-pyridineacetic acidhydrochloride by the method similar to that in Example 65. Yield: 70%.

[1995] Melting point: 122-127° C. (ethanol-diethyl ether).

[1996]¹H NMR (CDCl₃) δ1.23 (6H, br s), 1.30 (6H, s), 2.26 (2H, s), 2.67(2H, s), 3.67 (2H, s), 3.91 (3H, s), 6.59 (1H, s), 7.06 (1H, d, J=7.4Hz), 7.24-7.37 (3H, m), 7.64-7.80 (3H, m), 8.52-8.58 (2H, m).

Example 67

[1997]N-[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2-pyridineacetamide

[1998] The title compound.was obtained using 2-pyridineacetic acidhydrochloride by the method similar to that in Example 65. Yield: 75%.

[1999] Melting point: 176-177° C. (ethanol-diethyl ether).

[2000]¹H NMR (CDCl₃) δ1.24 (6H, br s), 1.29 (6H, s), 2.27 (2H, s), 2.68(2H, s), 3.87 (2H, s), 3.92 (3H, s), 6.60 (1H, s), 7.07 (1H, dt, J=7.7,1.3 Hz), 7.21-7.37 (3H, m), 7.42 (1H, t, J=1.6 Hz), 7.71 (1H, td, J=7.7,1.9 Hz), 7.80 (1H, ddd, J=8.2, 2.0, 0.8 Hz), 8.63 (1H, ddd, J=4.9, 1.8,1.1 Hz), 9.82 (1H, br s).

Example 68

[2001][[4-[[[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-5yl)phenyl]amino]carbonyl]phenyl]methyl]phosphonic acid diethyl esterhydrochloride

[2002] 1-Ethyl-3-(3-dimethylaminopropyl)carbodimide hydrochloride (1.55g, 8.09 mmol) and triethylamine (1.0 mL, 7.2 mmol) were added to asolution of3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine(2.18 g, 6.22 mmol), 4-[(diethoxyphosphinyl)methyl]benzoic acid (1.86 g,6.83 mmol) and 1-hydroxy-1H-benzotriazole monohydrate (1.05 g, 6.86mmol) in N,N-dimethylformamide (30 mL) and the mixture was stirred atroom temperature for 17 hours. The reaction mixture was combined withwater and a saturated aqueous solution of sodium. hydrogen carbonate,and extracted with ethyl acetate 3 times. The combined organic layer waswashed with water and brine, dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was subjected to acolumn chromatography on a basic silica gel (hexane/ethyl acetate 2:1,1:1, 1:3, followed-by 1:10) to obtain a free base of the title compound.This was dissolved in ethyl acetate (20 mL), combined with 0.8 Msolution of hydrogen chloride/methanol (8.5 mL), and concentrated underreduced pressure. The residue was recrystallized from ethanol-ethylacetate to obtain the title compound (3.23 g, Yield: 81%).

[2003] Melting point: 196-200° C. (decomposition).

[2004]¹H NMR (DMSO-d₆) δ1.18 (6H, t, J=7.1 Hz), 1.25 (6H, br s),1.37-1.58 (6H, m), 2.16-2.57 (2H, m), 3.05-3.35 (2H, m), 3.35 (2H, d,J=22.0 Hz), 3.89-4.05 (4H, m), 3.96 (3H, s), 7.12 (1H, s), 7.34-7.48(3H, m), 7.65 (1H, t, J=8.1 Hz), 7.97 (2H, d, J =8.0 Hz), 8.05-8.16 (2H,m), 10.69 (1H, br s), 12.60-12.80 (1H, br).

Example 69

[2005][[4-[[[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]amino]carbonyl]phenyl ]methyl]phosphonic acid

[2006] A solution of[[4-[[[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]amino]carbonyl]phenyl]methyl]phosphonicacid diethyl ester hydrochloride (1.60 g, 2.50 mmol) in dichloromethane(10 mL) was treated dropwise with trimethylsilyl bromide (1.0 mL, 7.6mmol), and stirred at room temperature for 22 hours. The reactionmixture was concentrated under reduced pressure, and the residue wasdissolved in methanol (7.5 mL) and diethyl ether (10 mL). Propyleneoxide (7.5 mL) was added to the resultant solution and the mixture wasstirred at room temperature. The precipitated crystals were recovered byfiltration to obtain the title compound (1.31g, Yield: 96%).

[2007] Melting point: 237-241° C.

[2008]¹H NMR (DMSO-d₆) δ1.20 (6H, s), 1.22 (6H, s), 2.34 (2H, br s),2.73 (2H, br s), 3.00 (2H, d, J=21.2 Hz), 3.84 (3H, s), 6.86 (1H, s),7.11 (1H, d, J=7.8 Hz), 7.33-7.46 (3H, m), 7.82-7.97 (4H, m), 10.32 (1H,br 8).

Example 70

[2009]2-Methyl-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2-[(2,2,2-trifluoroacetyl)amino]propanamidehydrochloride

[2010] The title compound was obtained using2-methyl-2-[(2,2,2-trifluoroacetyl)amino]propionic acid by the methodsimilar to that in Example 68. Yield: 89%.

[2011] Melting point: 210-217° C. (decomposition) (methanol-ethylacetate).

[2012]¹H NMR (DMSO-d₆) δ1.23 (6H, s), 1.30-1.60 (6H, m), 1.53 (6H, s),2.10-2.53 (2H, m), 3.00-3.35 (2H, m), 3.95 (3H, s), 711 (1H, s), 7.35(1H, d, J=8.0 Hz), 7.59 (1H, t, J=8.0 Hz), 7.91 (1H, s), 7.98 (1H, d,J=8.0 Hz), 9.44 (1H, br s), 10.16 (1H, br s), 12.60-12.80 (1H, br s).

Example 71

[2013]2-Amino-2-methyl-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]propanamide

[2014] 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.98g, 26.0 mmol) was added to a solution of3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine(7.01 g, 20.0 mmol), 2-methyl-2-[(2,2,2-trifluoroacetyl)amino]propionicacid (4.38 g, 22.0 mmol) and 1-hydroxy-1H-benzotriazole monohydrate(3.37 g, 22.0 mmol) in N,N-dimethylformamide (75 mL) and the mixture wasstirred at room temperature for 4.5 hours, and then at 45° C. for 30minutes. The reaction mixture was combined with water and a saturatedaqueous solution of sodium hydrogen carbonate, and extracted twice withethyl acetate. The combined organic layer was washed twice with water,and concentrated under reduced pressure. The residue was dissolved inethanol (40 mL), combined with 2 M aqueous solution of sodium hydroxide(25 mL, 50 mmol), and heated under reflux for 1.5 hours. The reactionmixture was concentrated under reduced pressure, and the residue wascombined with water, and extracted twice with ethyl acetate. Thecombined organic layer was washed twice with water, treated withactivated charcoal, filtered, and concentrated under reduced pressure.The residue was crystallized from ethyl acetate-hexane to obtain thetitle compound (7.28 g, Yield: 84%).

[2015] Melting point: 175-177° C.

[2016]¹H NMR (CDCl₃) δ1.24 (6H, br s), 1.32 (6H, s), 1.45 (6H, s), 2.30(2H, s), 2.67 (2H, br s), 3.92 (3H, s), 6.60 (1H, s), 7.04-7.10 (1H, m),7.33 (1H, t, J=8.1 Hz), 7.55 (1H, t, J=2.0 Hz), 7.83 (1H, ddd, J=8.1,2.0, 1.0 Hz), 9.93 (1H, br s).

Example 72

[2017]5,5-Dimethyl-3-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h,]isoquinolin-1-yl)phenyl]-2,4-imidazolidinedione

[2018] N,N′-carbonyldiimidazole (426 mg, 2.63 mmol) was added to asolution of2-amino-2-methyl-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]propanamide(1.09 g, 2.50 mmol) in N,N-dimethylformamide (10 mL) and the mixture wasstirred at room temperature for 2 hours. The reaction mixture wascombined with water and a saturated aqueous solution of sodium hydrogencarbonate, and extracted twice with ethyl, acetate. The combined organiclayer was washed twice with water, and concentrated under reducedpressure. The residue was crystallized from ethyl acetate-diethyl etherto obtain the title compound (686 mg, Yield: 59%).

[2019] Melting point::289-294° C.

[2020]¹H NMR (CDCl₃) δ1.28 (6H, br s), 1.33 (12H, s), 2.36 (2H, br s),2.70 (2H, s), 3.92 (3H, s), 6.61 (1H, s), 7.16 (1H, br s), 7.30-7.51(3H, m), 7.56-7.60 (1H, m).

Example 73

[2021]3-[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2,4-imidazolidinedione

[2022]3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine(3.51 g, 10.0 mmol) was added to a solution of ethyl isocyanatoacetate(1.42 g, 11.0 mmol) in tetrahydrofuran (15 mL) and the mixture washeated under reflux for 15 minutes. The reaction mixture wasconcentrated under reduced pressure, and the residue was dissolved in 5M hydrochloride (20 mL). The resultant mixture was stirred at 80° C. for2 hours. The mixture was cooled with ice, neutralized with conc. aqueousammonia, and extracted twice with ethyl acetate. The combined organiclayer was washed twice with water, and concentrated under reducedpressure. The residue was recrystallized from ethyl acetate-hexane, andfurthermore recrystallized from methanol-acetate-hexane to obtain thetitle compound (2.50 g, Yield: 58%).

[2023] Melting point; 214-216 C.

[2024]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.33 (6H, s), 2.37 (2H, br s), 2.68(2H, s), 3.92 (3H, s), 4.04 (2H, s), 6.22 (1H, br s), 6.60 (1H, s),7.39-7.57 (4H, m).

Example 74

[2025]1-Methyl-3-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2,4-imidazolidinedione

[2026] Sodium hydride (66% suspension in oil) (80 mg, 2.2 mmol) wasadded to a solution of3-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2,4-imidazolidinedione(867 mg, 2.00 mmol) in N,N-dimethylformamide (4 mL) with cooling in ice,and the mixture was stirred at room temperature for 15 minutes. Theresultant mixture was cooled with ice, treated dropwise with iodomethane(0.19 mL, 3.1 mmol), and stirred at room temperature for 45 minutes. Thereaction mixture was combined with water, and extracted twice with ethylacetate. The combined organic layer was washed twice with water, andconcentrated under reduced pressure. The residue was subjected to acolumn chromatography on a basic silica gel (hexane/ethyl acetate 2:1followed by 1:2) to obtain the title compound (724 mg, Yield: 81%).

[2027] Amorphous.

[2028]¹H NMR (CDCl₃) δ1.24 (6H, s), 1.33 (6H, s), 2.38 (2H, br s), 2.67(2H, s), 3.07 (3H, s), 3.91 (3H, s), 4.01 (2H, s), 6.59 (1H, s),7.39-7.55 (4H, m).

Example 75

[2029]2,4-Dioxo-3-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-1-imidazolidineaceticacid methyl ester

[2030] The title compound was obtained using methyl bromoacetate by themethod similar to that in Example 74. Yield: 77%.

[2031] Amorphous.

[2032]¹H NMR (CDCl₃) δ1.24 (6H, s), 1.33 (6H, s), 2.37 (2H, br s), 2.67(2H, s), 3.79 (3H, s), 3.92 (3H, s), 4.16 (2H, s), 4.24 (2H, s), 6.60(1H, s), 7.40-7.56 (4H, m).

Example 76

[2033]N-methyl-3-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2,4-dioxo-1-imidazolidineacetamide

[2034] 5 M aqueous solution of sodium hydroxide (1.5 mL) was added to asolution of3-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2,4-dioxo-1-imidazolidineaceticacid methyl ester (1.87 g, 3.70 mmol) in methanol (10 mL) and themixture was stirred at room temperature for 15 minutes. 2 M hydrochloricacid was added to the reaction mixture and the reaction mixture wasconcentrated under reduced pressure. The residue was combined withethanol, and the insolubles were filtered off, and filtrate wasconcentrated under reduced pressure. The same procedure was repeatedtwice, and then suspended in ethanol-ethyl acetate, filtered, andconcentrated under reduced pressure to obtain an amorphous material(2.08 g) containing3-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2,4-dioxo-1-imidazolidineaceticacid.

[2035] 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (312mg, 1.63 mmol) and 40% solution of methylamine/methanol (0.27 mL, 6.6mmol) were added to a solution of 700 mg of the material and1-hydroxy-1H-benzotoriazole monohydrate (211 mg, 1.38 mmol) inN,N-dimethylformamide (10 mL) with cooling in ice and the mixture wasstirred at room temperature for 43 hours. The reaction mixture wascombined with water and a saturated aqueous solution of sodium hydrogencarbonate, and extracted twice with ethyl acetate. The combined organiclayer was washed twice with water, and concentrated under reducedpressure. The residue was subjected to a column chromatography on abasic silica gel (hexane/ethyl acetate 1:1 followed by ethyl acetate) toobtain the title compound (289 mg, Yield: 46%).

[2036] Amorphous.

[2037]¹H NMR (CDCl₃) δ1.24 (6H, s), 1.33 (6H, s), 2.37 (2H, br s), 2.67(2H, s), 2.81 (3H, d, J=5.2 Hz), 3.92 (3H, s), 4.00 (2H, s), 4.18 (2H,s), 6.10-6.25 (1H, m), 6.60 (1H, s), 7.38-7.56 (4H, m).

Example 77

[2038]1-[1,1′-Biphenyl]-3-yl-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinoline

[2039] A solution of phenylboronic acid (219 mg, 1.80 mmol) in ethanol(2 mL), a solution of sodium carbonate (210 mg, 1.98 mmol) in water (2mL) and tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.050 mmol)were added to a solution of1-(3-bromophenyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoqulnoline(497 mg, 1.20 mmol) in 1,2-dimethoxyethane (6 mL) and the mixture wasstirred at 80° C. for 15 hours under nitrogen atmosphere. The reactionmixture was combined with water, and extracted twice with ethyl acetate.The combined organic layer was washed with water and brine, dried oversodium sulfate, filtered, and concentrated under reduced pressure. Theresidue as subjected to a column chromatography on a basic silica gel(hexane/ethyl acetate 10:1), and crystallized from hexane to obtain thetitle compound (353 mg, Yield: 71%).

[2040] Melting point: 141-142° C.

[2041]¹H NMR (CDCl₃) δ1.27 (6H, s), 1.30 (6H, s), 2.26 (2H, s), 2.71(2H, s), 3.93 (3H, s), 6.63 (1H, s), 7.28-7.51 (5H, m), 7.57-7.66 (4H,m).

Example 78

[2042]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-[3-(4-pyridinyl)phenyl]furo[2,3-h]isoquinoline

[2043] The title compound was obtained using 4-pyridinylboronic acid bythe method similar to that in Example 77. Yield: 69%.

[2044] Melting point: 148-150° C. (diisopropyl ether-hexane).

[2045]¹H NMR (CDCl₃) δ1.28 (6H, s), 1.30 (6H, s), 2.23 (2H, s), 2.72(2H, s), 3.93 (3H, s), 6.64 (1H, s), 7.44-7.57 (4H, m), 7.64-7.72 (2H,m), 8.66 (2H, d, J=6.2 Hz).

Example 79

[2046]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-[3-(2-quinolinyl)phenyl]furo[2,3-h]isoquinoline

[2047] Hexamethylditin (879 mg, 2.68 mmol) was added to a suspension of1-(3-bromophenyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinoline(1.04 g, 2.51 mmol), 2-quinolinyl trifluoromethanesulfonate (731 mg,2.64 mmol), lithium chloride (319 mg, 7.53 mmol) andtetrakis(triphenylphosphine)palladium(0) (145 mg, 0.125 mmol) in1,4-dioxane (15 mL), and stirred at 100° C. for 15.5 hours undernitrogen atmosphere. The reaction mixture was poured into a mixture of a10% aqueous solution of potassium fluoride (25 mL)/ethyl acetate (25mL), and stirred at room temperature for 2 hours. The insolubles werefiltered off, and the organic layer was separated, and the aqueous layerwas extracted with ethyl acetate. The combined organic layer was washedwith brine, dried over sodium sulfate, filtered, and concentrated underreduced pressure. The residue-was subjected to a column chromatographyon a basic silica gel (hexane/ethyl acetate 20:1, 5:1 followed by 3:1),and crystallized from ethyl acetate-hexane to obtain the title compound(529 mg, Yield: 46%).

[2048] Melting point: 167-169° C.

[2049]¹H NMR (CDCl₃) 1.28 (6H, s), 1.29 (6H, s), 2.34 (2H, s), 2.74 (2H,s), 3.94 (3H, s), 6.65 (1H, s), 7.48-7.62 (3H, m), 7.73 (1H, ddd, J=8.4,6.9, 1.5 Hz), 7.80-7.87 (1H, m), 7.93 (1H, d, J=8.4 Hz), 8.13-8.26 (3H,m), 8.29 (1H, dt, J=7.0, 1.8 Hz).

Example 80

[2050]3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid hydrochloride

[2051] 5 M aqueous solution of sodium hydroxide (2.0 mL, 10 mmol) wasadded to a suspension of3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid methyl ester (1.81 g, 4.60 mmol) in ethanol (5 mL) and the mixturewas stirred at room temperature for 4 hours. 1 M hydrochloric acid (10mL, 20 mmol) was added to the reaction mixture and the resultant mixturewas concentrated under reduced pressure. The residue was combined withethanol, and the insolubles were filtered off using Hyflo Super-Cell(trade name), and the filtrate was concentrated under reduced pressure.The same procedure was repeated twice, and then the residue wasrecrystallized from ethanol-ethyl acetate to obtain the title compound(1.92 g, quantitative).

[2052] Melting point: 184-191° C.

[2053]¹H NMR (DMSO-d₆) δ1.21 (6H, br s), 1.46 (6H, br s), 2.05-2.25 (2H,m), 3.17 (2H, br s), 3.95 (3H, s), 7.11 (1H, s), 7.77 (1H, t, J=7.6 Hz),7.86 (1H, d, J=7.6 Hz), 8.17 (1H, s), 8.27 (1H, s).

Example 81

[2054]4-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid hydrochloride

[2055] The title compound was obtained from4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid methyl ester by the method similar to that in Example 80. Yield:83%.

[2056] Melting point: 195-204° C. (ethanol-ethyl acetate).

[2057]¹H NMR (DMSO-d₆) δ1.31 (6H, s), 1.74 (6H, s), 2.15 (2H, s), 3.10(2H, s), 4.03 (3H, s), 6.76 (1H, s), 7.66 (2H, d, J=8.3 Hz), 8.11 (2H,d, J=8.3 Hz).

Example 82

[2058]4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid hydrochloride

[2059] The title compound was obtained from4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid methyl ester by the method similar to that in Example 80. Yield:99%.

[2060] Melting point: 206-217° C. (ethanol-ethyl acetate).

[2061]¹H NMR (DMSO-d₆) δ1.23 (6H, s), 1.37 (3H, t, J=6.9 Hz), 1.46 (6H,s), 2.16 (2H, s), 3.17 (2H, s), 4.25 (2H, q, J=6.9 Hz), 7.10 (1H, s),7.75 (2H, d, J=8.3 Hz), 8.16 (2H, d, J=8.3 Hz).

Example 83

[2062]N-(4-Methoxyphenyl)-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide

[2063] 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (300mg, 1.56 mmol) was added to a solution of4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid hydrochloride (500 mg, 1.20 mmol) and1-hydroxy-1H-benzotriazole-monohydrate (202 mg, 1.32 mmol) inN,N-dimethylformamide (3 mL) with cooling in ice and the mixture wasstirred for 20 minutes. 4-Methoxyaniline (177 mg, 1.44 mmol) was addedto the resultant mixture at the same temperature, and the mixture wasstirred at room temperature for 2 hours. The reaction mixture wascombined with water, and extracted twice with ethyl acetate. Thecombined organic layer was washed with water and brine, dried oversodium sulfate, filtered, and concentrated under reduced pressure. Theresidue was subjected to a column chromatography on a basic silica gel(hexane/ethyl acetate 2:1 followed by 1:1), and recrystallized fromethyl acetate-hexane to obtain the title compound (442 mg, Yield: 76%).

[2064] Melting point: 120-122° C.

[2065]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.32 (6H, s), 2.22 (2H, s), 2.71(2H, s), 3.83 (3H, s), 3.93 (3H, s), 6.63 (1H, s), 6.93 (2H, d, J=8.8Hz), 7.52 (2H, d, J=8.6 Hz), 7.57 (2H, d, J=9.2 Hz), 7.84 (1H, br s),7.90 (2H, d, J=8.4 Hz).

Example 84

[2066]4-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide.

[2067] The title compound was obtained using 4 M solution ofammonia/methanol by the method similar to that in Example 83. Yield:74%.

[2068] Melting point: 229-231° C. (ethyl acetate-hexane).

[2069]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.31 (6H, s), 2.19 (2H, s), 2.70(2H, s), 3.93 (3H, s), 5.50-6.50 (2H, m), 6.62 (1H, s), 7.49 (2H, d,J=8.4 Hz), 7.84 (2H, d, J=8.4 Hz).

Example 85

[2070]N-Methyl-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide

[2071] The title compound was obtained using.a 40% aqueous solution ofmethylamine by the method similar to that in Example 83. Yield: 77%.

[2072] Melting point: 168-169° C. (ethyl acetate-hexane).

[2073]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.30 (6H, s), 2.17 (2H, s), 2.70(2H, s), 3.04 (3H, d, J=5.2 Hz), 3.92 (3H, s), 6.32-6.43 (1H, m), 6.62(1H, s), 7.45 (2H, d, J=8.3 Hz), 7.78 (2H, d, J=8.3 Hz).

Example 86

[2074]3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide

[2075] The title compound was obtained from3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid hydrochloride and 4 M solution of ammonia/methanol by the methodsimilar to that in Example 83. Yield: 67%.

[2076] Melting point: 219-220° C. (methanol-diisopropyl ether).

[2077]¹H NMR (CDCl₃) δ1.25 (6H, br s), 1.30 (6H, s), 2.17 (2H, s), 2.69(2H, s), 3.93 (3H, s), 5.30-6.60 (2H, m), 6.62 (1H, s), 7.45-7.57 (2H,m), 7.84-7.87 (1H, m), 7.90 (1H, dt, J=6.9, 2.1 Hz).

Example 87

[2078]4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide

[2079] The title compound was obtained from4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid hydrochloride and 4 M solution of ammonia/methanol by the methodsimilar to that in Example 83. Yield: 71%.

[2080] Melting point: 179-182° C. (ethyl acetate-hexane).

[2081]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.30 (6H, s), 1.46 (3H, t, J=6.9Hz), 2.17 (2H, s), 2.68 (2H, s), 4.19 (2H, q, J=6.9 Hz), 5.50-6.50 (2H,m), 6.61 (1H, s), 7.28 (2H, d, J=8.6 Hz), 7.84 (2H, d, J=8.6 Hz).

Example 88

[2082]N-Phenyl-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamidehydrochloride

[2083] 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (300mg, 1.56 mmol) was added to a solution of4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid hydrochloride (500 mg, 1.20 mmol) and 1-hydroxy-1H-benzotriazolemonohydrate (202 mg, 1.32 mmol) in N,N-dimethylformamide (3 mL) withcooling in ice and the mixture was stirred for 25 minutes Aniline (0.13mL, 1.4 mmol) was added to the resultant mixture at the sametemperature, and the mixture was stirred at room temperature for 2hours. The reaction mixture was combined with water and a saturatedaqueous solution of sodium hydrogen carbonate, and extracted twice withethyl acetate. The combined organic layer was washed with water andbrine, dried over sodium sulfate, filtered, and concentrated underreduced pressure. The residue was subjected to a column chromatographyon a basic silica gel (hexane/ethyl acetate 2:1 followed by 1:1) toobtain a free base of the title compound. This was dissolved in ethylacetate (5 mL), combined with 0.8 M solution of hydrogenchloride/methanol (2.1 mL), and concentrated under reduced pressure toobtain the title compound (537 mg, Yield: 91%).

[2084] Amorphous.

[2085]¹H NMR (CDCl₃) δ1.31 (6H, s), 1.64 (6H, s), 2.24 (2H, s), 3.07(2H, s), 4.01 (3H, s), 6.72 (1H, s), 7.11 (1H, t, J=7.4 Hz), 7.33 (2H,t, J=7.9 Hz), 7.60 (2H, d, J=8.0 Hz), 7.92 (2H, d, J=7.6 Hz), 8.18 (2H,d, J=7.6 Hz), 9.96 (1H, br s).

Example 89

[2086]N,N-Dimethyl-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamidehydrochloride

[2087] The title compound was obtained using a 50% aqueous solution ofdimethylamine by the method similar to that in Example 88. Yield: 88%.

[2088] Amorphous.

[2089]¹H NMR (CDCl₃) δ1.36 (6H, s), 1.69 (6H, s), 2.35 (2H, s), 3.01(3H, br s), 3.05 (2H, s), 3.13 (3H, br s), 4.03 (3H, s), 6.75 (1H, s),7.61 (2H, d, J=8.4 Hz), 7.72 (2H, d, J=8.4 Hz), 14.20-14.60 (1H, br).

Example 90

[2090][[(4-[[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoyl]amino]phenyl]methyl]phosphonicacid diethyl ester

[2091] 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (748mg, 3.90 mmol) and triethylamine (1.0 mL, 7.2 mmol) were added to asolution of3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid hydrochloride (1-37 g, 3.29 mmol), diethyl 4-aminobenzylphosphonate(730 mg, 3.00 mmol) and 1-hydroxy-1H-benzotriazole monohydrate (506 mg,3.30 mmol) in N,N-dimethylformamide (15 mL) and the mixture was-stirredat room temperature for 18 hours. The reaction mixture was combined withwater and a saturated aqueous solution of sodium hydrogen carbonate, andextracted twice with ethyl acetate. The combined organic layer waswashed twice with water and concentrated under reduced pressure. Theresidue was subjected to a column chromatography on a basic silica gel(hexane/ethyl acetate 1:1 followed by 1:5) to obtain the title compound(1.16 g, Yield: 64%).

[2092] Amorphous.

[2093]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.25 (6H, t, J=7.1 Hz), 1.31 (6H,s), 2.22 (2H, s), 2.68 (2H, s), 3.14 (2H, d, J=21.6 Hz), 3.92-4.10 (4H,m), 3.93 (3H, s), 6.63 (1H, s), 7.24-7.34 (2H, m), 7.46-7.53 (2H, m),7.64 (2H, d, J=8.0 Hz), 7.94-8.02 (2H, m), 8.63 (1H, br s).

Example 91

[2094]3,4,8,9-Tetrahydro-3,3.8,8-tetramethyl-1-phenyl-6-furo[2.3-h]isoquinolinolhydrobromide

[2095] 48% Hydrobromic acid (7.5 mL) was added to3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinoline(500 mg, 1.49 mmol) and the mixture was stirred at 105° C. for 18 hours.The reaction mixture was cooled, and the precipitated crystals wererecovered by filtration, washed with water, and then air-dried overnightto obtain the title compound (463 mg, Yield: 77%).

[2096]¹H NMR (DMSO-d₆) δ1.23 (6H, s), 1.42 (6H, s), 2.15 (2H, s), 3.09(2H, s), 6.79(1H, s), 7.57-7.80 (5H, m), 11.2-11.4 (1H, br), 12.1-12.4(1H, br).

Example 92

[2097]3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-1-phenyl-6-furo[2,3-h]isoquinolinol.

[2098] 4.8% Hydrobromic acid (45 mL) was added to3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinoline(3.02 g, 9.00 mmol) and the mixture was heated under reflux for 16hours. The reaction mixture was cooled with ice, neutralized with conc.aqueous ammonia, diluted with water, and extracted with ethyl acetate 3times. The combined organic layer was washed with brine, dried oversodium sulfate, treated with activated charcoal, filtered andconcentrated under reduced pressure. The residue was crystallized fromethyl acetate-diisopropyl ether to obtain the title compound (2.70 g,Yield: 93%).

[2099] Melting point: 208-210° C.

[2100]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.28 (6H, s), 2.16 (2H, s), 2.66(2H, s), 6.54 (1H, s), 7.38 (5H, m).

Example 93

[2101]3,4,8,9-Tetrahydro-1-(4-hydroxyphenyl)-6-methoxy-3,3,8,8-tetramethyl-6-furo[2,3-h]isoquinolinolhydrobromide

[2102] The title compound was obtained from3,4,8,9-tetrahydro-6-methoxy-1-(4-methoxyphenyl)-3,3,8,8-tetramethylfuro[2,3-h]isoquinolineby the method similar to that in Example 91. Yield: 77%.

[2103] Melting point: 194-200° C.

[2104]¹H NMR (DMSO-d₆) δ1.27 (6H, s), 1.38 (6H, s), 2.34 (2H, s), 3.03(2H, s), 6.77 (1H, s), 6.99 (2H, d, J=8.4 Hz), 7.46 (2H, d, J=8.4 Hz),10.59 (1H, s), 11.17 (1H, br s), 11.80-11.95 (1H, br).

Example 94

[2105]1-(3-Bromophenyl)-3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-6-furo[2,3-h]isoquinolinol

[2106] The title compound was obtained from1-(3-bromophenyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolineby the method similar to that in Example 92. Yield: 91%.

[2107] Melting point: 202-208° C. (ethyl acetate-diisopropyl ether).

[2108]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.32 (6H, s), 2.22 (2H, s), 2.63(2H, s), 6.52 (1H, s), 7.24 (1H, t, J=7.6 Hz), 7.34 (1H, dt, J=7.6, 1.4Hz), 7.47-7.54 (1H, m), 7.57 (1H, t, J=1.4 Hz).

Example 95

[2109] Trifluoromethanesulfonic acid(3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin-6-yl)ester

[2110] A solution of3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenyl-6-furo[2.3-h]isoquinolinol(1.03 g, 3.20 mmol) in pyridine (10 mL) was treated dropwise withtrifluoromethanesulfonic anhydride (0.60 mL, 3.6 mmol) with cooling inice, and stirred for 10 minutes. The reaction mixture was combined withwater and a saturated aqueous solution of sodium hydrogen carbonate, andextracted twice with ethyl acetate. The combined organic layer waswashed twice with water, and concentrated under reduced pressure. Theresidue was subjected to a column chromatography on a basic silica gel(hexane/ethyl acetate 10:1) to obtain the title compound (1.37 g, Yield:94%).

[2111] An oil.

[2112]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.30 (6H, s), 2.23 (2H, s), 2.70(2H, s), 6.94 (1H, s), 7.41 (5H, s).

Example 96

[2113] Trifluoromethanesulfonic acid(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-6-yl)esterhydrochloride

[2114] The title compound was obtained from trifluoromethanesulfonicacid(3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin-6-yl)esterby the method similar to that in Example 29. Yield: 84%.

[2115] Melting point: 152-160° C. (methanol-ethyl acetate).

[2116]¹H NMR (DMSO-d₆) δ1.28 (6H, s), 1.43 (6H, br s), 2.32 (2H, s),3.17 (2H, br s), 7.56 (1H, s), 7.57-7.83 (5H, m).

Example 97

[2117]3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolinehydrochloride

[2118] Formic acid (0.17 mL, 4.5 mmol) was added to a solution oftrifluoromethanesulfonic acid(3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin-6-yl)ester(1.00 g, 2.21 mmol), triethylamine (0.92 mL, 6.6 mmol), palladium(II)acetate (9.9 mg, 0.044 mmol) and triphenylphosphine (23.1 mg, 0.0881mmol) in N,N-dimethylformamide (4 mL) and the mixture was stirred at 60°C. for 3.5 hours under nitrogen atmosphere. The reaction mixture wascombined with water, and extracted twice with ethyl acetate. Thecombined organic layer was extracted twice with 1 M hydrochloric acid.The combined aqueous layer was neutralized with conc. aqueous ammonia,and extracted twice with ethyl acetate. The combined organic layer waswashed with brine, dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The residue was subjected to a columnchromatography on a basic silica gel (hexane/ethyl acetate 15:1) toobtain a free base of the title compound. The mixture was dissolved inethyl acetate (3 mL), and combined with 0.8 M solution of hydrogenchloride/methanol (3.0 mL). The resultant mixture was concentrated underreduced pressure, and the residue was crystallized from ethylacetate-diisopropyl ether to obtain the title compound (705 mg, Yield:93%).

[2119] Melting point: 167-179° C.

[2120]¹H NMR (DMSO-d₆) δ1.23 (6H, s), 1.46 (6H, s), 2.19 (2H, s), 3.16(2H, s), 7.17 (1H, d, J=8.1 Hz), 7.30 (1H, d, J=8.1 Hz), 7.62-7.84 (5H,m).

Example 98

[2121]3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-1-[3-(4-pyridinyl)phenyl]-6-furo[2,3-h]isoquinolinol

[2122] A solution of sodium carbonate (480 mg, 4.53 mmol) in water (5mL) and tetrakis(triphenylphosphine)palladium(0) (105 mg, 0.0909 mmol)were added to a suspension of1-(3-bromophenyl)-3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-6-furo[2,3-h]isoquinolinol(725 mg, 1.81 mmol) and 4-pyridinylboronic acid (334 mg, 2.72 mmol) intoluene (10 mL) and ethanol (3 mL) and the mixture was stirred at 90° C.for 15 hours under nitrogen atmosphere. The reaction mixture was cooledand combined with 1 M hydrochloric acid, and the insolubles werefiltered off, and the organic layer was separated. The aqueous layer wasneutralized with conc. aqueous ammonia, and extracted twice with ethylacetate. The combined organic layer was washed with brine, dried oversodium sulfate, filtered, and concentrated under reduced pressure. Theresidue was subjected to a column chromatography on a basic silica gel(ethyl acetate followed by ethyl acetate/methanol 20:1), andcrystallized from ethyl acetate-diisopropyl ether to obtain the titlecompound (294 mg, Yield: 41%).

[2123] Melting point: 141-149° C.

[2124]¹H NMR (CDCl₃) δ1.27 (12H, s), 2.21 (2H, s), 2.67 (2H, s), 6.58(1H, s), 7.43-7.58 (4H, m), 7.64-7.73 (2H, m), 8.66 (2H, d, J=6.2 Hz).

Example 99

[2125]3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-6-propoxy-1-[3-(4-pyridinyl)phenyl]furo[2,3-h]isoquinoline

[2126] Sodium hydride (66% suspension in oil) (95 mg, 2.6 mmol) wasadded to a solution of3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-[3-(4-pyridinyl)phenyl]-6-furo[2,3-h]isoquinolinol(812 mg, 2.00 mmol) and 1-iodopropane (0.59 mL, 6.0 mmol) inN,N-dinethylformamide (4 mL) and the mixture was stirred at roomtemperature for 30 minutes. The reaction mixture was poured into water,and extracted twice with ethyl acetate. The combined organic layer waswashed with water.and brine, dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was subjected to acolumn chromatography on a basic silica gel (hexane/ethyl acetate 10:1followed by 2:1), and recrystallized from ethyl acetate-hexane to obtainthe title compound (614 mg, Yield: 70%).

[2127] Melting point: 132-134° C.

[2128]¹H NMR (CDCl₃) δ1.04 (3H, t, J=7.5 Hz), 1.27 (6H, s), 1.30 (6H,s), 1.87 (2H, sixtet, J=7.2 Hz), 2.21 (2H, s), 2.70 (2H, s), 4.07 (2H,t, J=6.9 Hz), 6.63 (1H, s), 7.43-7.57 (4H, m), 7.64-7.71 (2H, m), 8.66(2H, d, J=6.0 Hz).

Example 100

[2129]2-[[3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-1-[3-(4-pyridinyl)phenyl]furo[2,3-h]isoquinolin-6-yl]oxy]acetamide

[2130] The title compound was obtained using 2-bromoacetamide by themethod similar to that in Example 99. Yield: 63%.

[2131] Melting point: 120-125° C. (ethyl acetate-hexane).

[2132]¹H NMR (CDCl₃) δ1.28 (6H, s), 1.30 (6H, s), 2.24 (2H, s), 2.71(2H, s), 4.63 (2H, s), 5.55-5.85 (1H, br), 6.65 (1H, s), 6.70-6.95 (1H,br), 7.43-7.59 (4H, m), 7.64-7.73 (2H, m), 8.67 (2H, d, J=6.4 Hz).

Example 101

[2133]1-(3-Bromophenyl)-6-ethoxy-3,4,8,9-tetrahydro-3,3.8,8-tetramethylfuro[2,3-h]isoquinoline

[2134] The title compound was obtained from1-(3-bromophenyl)-3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-6-furo[2,3-h]isoquinolinoland iodomethane by the method similar to that in Example 99.Quantitative.

[2135] Amorphous.

[2136]¹H NMR (CDCl₃) δ1.23 (6H, s), 1.34 (6H, s), 1.46 (3H, t, J=7.1Hz), 2.22 (2H, s), 2.66 (2H, s), 4.18 (2H, q, J=7.1 Hz), 6.60 (1H, s),7.25 (1H, t, J=7.5 Hz), 7.33 (1H, dt, J=7.5, 1.7 Hz), 7.52 (1H, dt,J=7.5, 1.7 Hz), 7.57 (1H, t, J=1.7 Hz).

Example 102

[2137]1-(3-Bromophenyl)-6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolinehydrochloride

[2138] The title compound was obtained from1-(3-bromophenyl)-6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolineby the method similar to that in Example 29. Yield: 74%.

[2139] Melting point: 219-223° C. (sealed tube) (methanol-ethylacetate-diethyl ether).

[2140]¹H NMR (DMSO-d₆) δ1.25 (6H, s), 1.37 (3H, t, J=7.0 Hz), 1.44 (6H,br s), 2.22 (2H, s), 3.12 (2H, br s), 4.24 (2H, g, J=7.0 Hz), 7.08 (1H,s), 7.52-7.65 (2H, m), 7.88-7.99 (2H, m).

Example 103

[2141]1-(3-Bromophenyl)-6-butoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinoline

[2142] The title compound was obtained from1-(3-bromophenyl)-3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-6-furo[2,3-h]isoquinolinoland 1-iodobutane by the method similar to that in Example 99. Yield:84%.

[2143] Gummy.

[2144]¹H NMR (CDCl₃) δ0.98 (3H, t, J=7.2 Hz), 1.23 (6H, s), 1.33 (6H,s), 1.38-1.59 (2H, m), 1.74-1.90 (2H, m), 2.21 (2H, s), 2.66 (2H, s),4.10 (2H, t, J=6.8 Hz), 6.60 (1H, s), 7.20-7.29 (1H, m), 7.34 (1H, dt,J=7.5, 1.5 Hz), 7.48-7.55 (1H, m), 7.57 (1H, t, J=1.5 Hz).

Example 104

[2145]1-(3-Bromophenyl)-6-butoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolinehydrochloride

[2146] The title compound was obtained from1-(3-Bromophenyl)-6-butoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolineby the method similar to that in Example 29. Yield: 75%.

[2147] Melting point: 201-205° C. (sealed tube) (methanol-ethylacetate-diethyl ether).

[2148]¹H NMR (DMSO-d₆) δ0.94 (3H, t, J=7.2 Hz), 1.20-1.60 (8H, m), 1.25(6H, s), 1.65-1.82 (2H, m), 2.21 (2H, s), 3.12 (2H, br s), 4.18 (2H, t,J=6.5 Hz), 7.10 (1H, s), 7.48-7.66 (2H, m), 7.90-7.99 (2H, m),12.50-13.00 (1H, br).

Example 105

[2149]6-Butoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-[3-(4-pyridinyl)phenyl]furo[2,3-h]isoquinoline

[2150] A solution of sodium carbonate (5.10 g, 48.1 mmol) in water (45mL) and tetrakis(triphenylphosphine)palladium(0) (1.69 g, 1.46 mmol)were added to a suspension of1-(3-bromophenyl)-6-butoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinoline(18.2 g, 39.9 mmol) and 4-pyridinylboronic acid (5.38 g, 43.8 mmol) inN,N-dimethylformamide (75 mL) and the mixture was stirred at 120° C. for1.5 hours under nitrogen atmosphere. The reaction mixture was cooled andcombined with water and ethyl acetate, and the organic layer wasseparated, and the aqueous layer was extracted with ethyl acetate. Thecombined organic layer was washed twice with water, and concentratedunder reduced pressure. The residue was subjected to a columnchromatography on a basic silica gel (hexane/ethyl acetate 10:1 followedby 2:1), and recrystallized from diethyl ether-hexane to obtain thetitle compound (9.12 g, Yield: 50%).

[2151] Melting point: 114-116° C.

[2152]¹H NMR (CDCl₃) δ0.98 (3H, t, J=7.3 Hz), 1.27 (6H, s), 1.29 (6H,s), 1.39-1.60 (2H, m), 1.75-1.92 (2H, m), 2.21 (2H, s), 2.70 (2H, s),4.11 (2H, t, J=6.9 Hz), 6.63 (1H, s), 7.45-7.57 (4H, m), 7.64-7.72 (2H,m), 8.66 (2H, d, J=6.2 Hz).

Example 106

[2153]6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-[3-(4-pyridinyl)phenyl]furo[2,3-h]isoquinoline

[2154] The title compound was obtained from1-(3-bromophenyl)-6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolineby the method similar to that in Example 105. Yield: 59%.

[2155] Melting point: 102-104° C. (diethyl ether-hexane).

[2156]¹H NMR (CDCl₃) δ1.27 (6H, s), 1.30 (6H, s), 1.47 (3H, t, J=7.0Hz), 2.22 (2H, s), 2.70 (2H, s), 4.19 (2H, q, J=7.0 Hz), 6.63 (1H, s),7.42-7.58 (4H, m), 7.65-7.71 (2H, m), 8.66 (2H, d, J=6.0 Hz).

Example 107

[2157]6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolinehydrochloride

[2158] A free base of the title compound was obtained from3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenyl6-furo[2,3-h]isoquinolinoland iodomethane by the method similar to that in Example 99. This wasdissolved in ethyl acetate, combined with 0.8 M solution of hydrogenchloride/methanol, and concentrated under reduced pressure to obtain thetitle compound. Quantitative.

[2159] Amorphous.

[2160]¹H NMR (CDCl₃) δ1.33 (6H, s), 1.51 (3H, t, J=7.0 Hz), 1.69 (6H,s), 2.23 (2H, s), 3.02 (2H, s), 4.28 (2H, q, J=7.0 Hz), 6.73 (1H, s),7.50-7.75 (5H, m).

Example 108

[2161]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenyl-4-furo[2,3-h]isoquinolinol

[2162] Aluminum chloride (0.68 g, 5.1 mmol) was added to a solution of2,3-dihydro-7-methoxy-2,2-dimethyl-5-(2-methyl-1-propenyl)benzofuran(1.17 g, 5.04 mmol) in benzonitrile (10 mL) at −10° C. and the mixturewas stirred at the same temperature for 5 minutes. The resultant mixturewas treated dropwise with bromine (0.26 mL, 5.0 mmol), and stirred atroom temperature for 20 minutes and then at 60° C. for 2 hours. Thereaction. mixture was cooled, combined with water and diisopropyl ether,stirred, and then the organic layer was separated. The aqueous layer wasneutralized with conc. aqueous ammonia, combined with ethyl acetate, andthen the insolubles were filtered off. The aqueous layer was separated,and the organic layer was washed with brine, dried over sodium sulfate,filtered, and concentrated under reduced pressure. The residue wasrecrystallized from tetrahydrofuran diethyl ether to obtain the titlecompound (722 mg, Yield: 41%)

[2163] Melting point: 207-212° C.

[2164]¹H NMR (CDCl₃) δ1.25 (3H, s) 1.31 (6H, s), 1.32 (3H, s), 2.21 (2H,s), 3.96 (3H, s), 4.48 (1H, br s), 6.96 (1H, s), 7.40 (5H, s).

Example 109

[2165]3-(Bromomethyl)-3,4,8,9-tetrahydro-6-methoxy-3,8,8-triethyl-1-phenylfuro[2,3-h]isoquinoline

[2166] Aluminum chloride (1.01 g, 7.57 mmol) was added to a solution of2,3-dihydro-7-methoxy-2,2-dimethyl-5-(2-methyl-2-propenyl)benzofuran(1.76 g, 7.58 mmol) in benzonitrile (15 mL) at −5° C. and the mixturewas stirred at the same temperature for 5 minutes. The resultant mixturewas treated dropwise with bromine (0.39 mL, 7.6 mmol), and stirred atroom temperature for 25 minutes and then at 60° C. for 30 minutes. Thereaction mixture was cooled, combined with water and diisopropyl ether,stirred, and then the aqueous layer was separated, and the organic layerwas extracted twice with 1 M hydrochloric acid. The combined aqueouslayer was neutralized with conc. aqueous ammonia with cooling in ice,and extracted twice with ethyl acetate. The combined organic layer waswashed with water and brine, dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was subjected to acolumn chromatography on a silica gel (hexane-ethyl acetate 10:1), andcrystallized from diethyl ether-hexane to obtain the title compound (297mg, Yield: 9.5%).

[2167] Melting point: 108-110° C.

[2168]¹H NMR (CDCl₃) δ1.31 (6H, s), 1.34 (3H, s), 2.20 (2H, s), 2.80(1H, d, J=15.8 Hz), 2.96 (1H, d, J=15.8 Hz), 3.41 (1H, d, J =9.9 Hz),3.57 (1H, d, J=9.9 Hz), 3.93 (3H, s), 6.60 (1H, s), 7.40 (5H, s).

Example 110

[2169]6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinoline2-oxide

[2170] A solution of sodium tungstate(VI) dihydrate (310 mg, 0.940 mol)in water (3 mL) was added to a solution of6-ethoxy-1,2,3,4,8,9-hexahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinoline(1.65 g, 4.69 mmol) in methanol (10 mL). This was cooled, treateddropwise with 30% aqueous hydrogen peroxide (1.6 g, 14 mmol), andstirred at room temperature for 15 hours. The reaction mixture wascombined with water, and extracted with ethyl acetate 3 times. Thecombined organic layer was washed with water, a 10% aqueous solution ofsodium thiosulfate and brine, dried over magnesium sulfate, filtered,and concentrated under reduced pressure. The residue was subjected to acolumn chromatography on a basic silica gel (hexane/ethyl acetate 5:1followed by 1:1), and crystallized from diisopropyl ether-hexane toobtain the title compound (1.33 g, Yield: 78%).

[2171] Melting point: 125-126° C.

[2172]¹H NMR (CDCl₃) δ1.27 (6H, s), 1.45 (3H, t, J=7.0 Hz), 1.48 (6H,s), 1.98 (2H, s), 3.04 (2H, s), 4.16 (2H, q, J=7.0 Hz), 6.62 (1H, s),7.32-7.47 (5H, m).

Example 111

[2173]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinoline2-oxide

[2174] The title compound was obtained from1,2,3,4,8,9-hexahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolineby the method similar to that in Example 110. Yield: 84%.

[2175] Melting point: 177-180° C. (diisopropyl ether).

[2176]¹H NMR (CDCl₃) δ1.28 (6H, s), 1.49 (6H, s), 1.99 (2H, s), 3.06(2H, s), 3.91 (3H, s), 6.63 (1H, s), 7.27-7.47 (5H, m).

Example 112

[2177]4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-2-oxidefuro[2,3-h]isoquinolin-1-yl)benzamide

[2178] The title compound was obtained from4-(6-ethoxy-1,2,3,4,8,9-hexahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamideby the method similar to that in Example 110. Yield: 83%.

[2179] Melting point: 134-136, 218-219° C. (ethyl acetate-diisopropylether).

[2180]¹H NMR (CDCl₃), δ1.28 (6H, s), 1.46 (3H, t, J=7.1 Hz), 1.48 (6H,s), 2.00 (2H, s), 3.06 (2H, s), 4.17 (2H, q, J=7.1 Hz), 5.40-6.50 (2H,m), 6.64 (1H, s), 7.55 (2H, d, J=8.4 Hz), 7.89 (2H, d, J=8.4 Hz).

Example 113

[2181]5-[(Dimethylamino)methyl]-3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenyl-6-furo[2,3-h]isoquinolinol

[2182] A mixture of3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenyl-6-furo[2,3-h]isoquinolinol(1.50 g, 4.67 mmol), paraformaldehyde (94%) (0.298 g, 9.34 mmol), a 2 Msolution of dimethylamine/tetrahydrofuran (7.00 mL, 14.0 mmol) andethanol (7 mL) was stirred at 60° C. for 20 minutes. The reactionsolution was concentrated under reduced pressure, and the residue wassubjected to a column chromatography on a basic silica gel (hexane/ethylacetate 3:1), and recrystallized from hexane-ethyl acetate to obtain thetitle compound (1.38 g, Yield: 78%)

[2183] Melting point: 164-166° C.

[2184]¹H NMR (CDCl₃) δ1.23 (6H, s), 1.30 (6H, s), 2.14 (2H, s), 2.38(6H, s), 2.58 (2H, s), 3.74 (2H, s), 7.37 (5H, s).

Example 114

[2185]3,4,8,9-Tetrahydro-6-methoxy-N,N,3,3,8,8-hexamethyl-1-phenyl-5-furo[2,3-h]isoquinolinemethanamine

[2186] Diisopropyl azodicarboxylate (0.624 mL, 3.18 mmol) was added to asolution of5-[(dimethylamino)methyl]-3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenyl-6-furo[2,3-h]isoquinolinol(0.40 g, 1.06 mmol), methanol (0.128 mL, 3.18 mmol) andtriphenylphosphine (0.832 g, 3.18 mmol) in tetrahydrofuran (3 mL) withcooling in ice, and the mixture was stirred at room temperature for 30minutes. The reaction solution was combined with 1 M hydrochloric acid,and washed with ethyl acetate. The aqueous layer was basified with 1 Maqueous solution of sodium hydroxide, and then extracted with ethylacetate. The extract was washed with water, and then concentrated underreduced pressure. The residue was subjected to a column chromatographyon a basic silica gel (hexane/ethyl acetate 9:1) to obtain the titlecompound (0.40 g, Yield: 96%). An aliquot was recrystallized fromhexane.

[2187] Melting point: 124-125° C.

[2188]¹H NMR (CDCl₃) δ1.23 (6H, s), 1.27 (6H, s), 2.13 (2H, s), 2.25(6H, s), 2.77 (2H, s), 3.45 (2H, s), 3.92 (3H, s), 7.38 (5H, s).

Example 115

[2189]3,4,8,9-Tetrahydro-6-methoxy-N,N,N,3,3,8,8-heptamethyl-1-phenyl-5-furo[2,3-h]isoquinolinemethanaminiumiodide

[2190] Iodomethane (0.309 mL, 4.97 mmol) was added to a solution of3,4,8,9-tetrahydro-6-methoxy-N,N,3,3,8,8-hexamethyl-1-phenyl-5-furo[2,3-h]isoquinolinemethanamine(1.50 g, 3.82 mmol) in toluene (10 mL) and the-mixture was stirred atroom temperature for 15 hours. The reaction solution was combined withhexane, and the precipitated crystals were recovered by filtration,dried, and then recrystallized from ethanol-ethyl acetate-hexane toobtain the title compound (1.90 g, Yield: 93%).

[2191] Melting point: 174-178° C.

[2192]¹H NMR (DMSO-d₆) δ1.17 (6H, s), 1.26 (6H, s), 2.21 (2H, s), 2.78(2H, s), 3.07 (9H, s), 3.94 (3H, s), 4.60 (2H, s), 7.37-7.46 (5H, m).

Example 116

[2193]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenyl-5-[(phenylthio)methyl]furo[2,3-h]isoquinolinehydrochloride

[2194] Sodium hydride (66% suspension in oil) (68.0 mg, 1.87 mmol) wasadded to a solution of thiophenol (0.192 mL, 1.87 mmol) inN,N-dimethylformamide (3 mL) with cooling in ice, and the mixture wasstirred at room temperature for 30 minutes.3,4,8,9-Tetrahydro-6-methoxy-N,N,N,3,3,8,8-heptamethyl-1-phenyl-5-furo[2,3-h]isoquinolinemethanaminiumiodide (0.40 g, 0.748 mmol) was added to the mixture, and the mixturewas stirred at 70° C. for 1 hour. The reaction solution was combinedwith water, and extracted with ethyl acetate. The extract was washedwith 1 M aqueous solution of sodium hydroxide and water, and thenconcentrated under reduced pressure. The residue was subjected to acolumn chromatography on a silica gel (hexane/ethyl acetate 7:3) toobtain a free base (0.31 g, Yield: 91%) of the title compound as an oil.

[2195]¹H NMR (CDCl₃) δ1.23 (6H, s), 1.28 (6H, s), 2.13 (2H, s), 2.67(2H, s), 3.92 (3H, s), 4.24 (2H, s), 7.18-7.45 (10H, m).

[2196] This was converted into a hydrochloride with 4 M solution ofhydrogen chloride/ethyl acetate, and then concentrated under reducedpressure to obtain the title compound (0.31 g, Yield: 84%).

[2197] Amorphous.

[2198]¹H NMR (DMSO-d₆) δ1.25 (6H, s), 1.43 (6H, s), 2.15 (2H, s), 3.15(2H, s), 3.90 (3H, s), 4.29 (2H, s), 7.25-7.45 (5H, m), 7.62-7.80 (5H,m).

Example 117

[2199] 6-Ethoxy-3,4,8,9-tetrahydro-N,N,3,3,8,8-hexamethyl-1-phenyl5-furo[2,3-h]isoquinolinemethanamine

[2200] The title compound was obtained using ethanol by the methodsimilar to that in Example 114. Yield: 89%.

[2201] Melting point: 106-107° C. (hexane).

[2202]¹H NMR (CDCl₃) δ1.23 (6H, s), 1.25 (6H, s), 1.36 (3H, t, J=7.2Hz), 2.12 (2H, s), 2.25 (6H, s), 2.77 (2H, s), 3.46 (2H, s), 4.19 (2H,q, J=7.2 Hz), 7.37 (5H, s).

Example 118

[2203]5-[(Dimethylamino)methyl]-3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin-6-ylacetate

[2204] Acetic anhydride (82.3 μL, 0.872 mmol) was added to a solution of5-[(dimethylamino)methyl]-3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenyl-6-furo[2,3-h]isoquinolinol(0.30 g, 0.793 mmol) in pyridine (3 mL), and the mixture was stirred atroom temperature. for 1 hour. The reaction solution was combined withwater, and extracted with ethyl acetate. The extract was washed withwater, and then concentrated under reduced pressure. The residue wasrecrystallized from hexane to obtain the title compound (0.24 g, Yield:72%).

[2205] Melting point: 125-126° C.

[2206]¹H NMR (CDCl₃) δ1.25 (12H, s), 2.17 (2H, s), 2.21 (6H, s), 2.31(3H, s), 2.79 (2H, s), 3.33 (2H, s), 7.38 (5H, s).

Example 119

[2207]3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-1-phenyl-5-[(1-pyridinyl)methyl]-6-furo[2,3-h]isoquinolinol

[2208] The title compound was obtained using piperidine by the methodsimilar to that in Example 113. Yield: 85%.

[2209] Melting point: 164-165° C.

[2210]¹H NMR (CDCl₃) δ1.22 (6H, s), 1.29 (6H, s), 1.40-1.72 (6H, m),2.14 (2H, s), 2.40-2.79 (4H, m), 2.56 (2H, s), 3.76 (2H, s), 5.32 (1H,br s), 7.37 (5H, s).

Example 120

[2211]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenyl-5-[(1-piperidinyl)methyl]furo[2,3-h]isoquinolinedihydrochloride

[2212] A free base of the title compound was obtained as an oil 5 from3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenyl-5-[(1-piperidinyl)methyl]-6-furo[2,3-h]isoquinolinolby the method similar to that in Example 114. Yield: 85%.

[2213]¹H NMR (CDCl₃) δ1.23 (6H, s), 1.28 (6H, s), 1.37-1.60 (6H, m),2.13 (2H, s), 2.37-2.44 (4H, m), 2.82 (2H, s), 3.48 (2H, s), 10 3.89(3H, s), 7.38 (5H, s).

[2214] This free base was converted into a hydrochloride with 4 Msolution of hydrogen chloride/ethyl acetate, and then concentrated underreduced pressure to obtain the title compound. Yield: 80%.

[2215] Amorphous.

[2216]¹H NMR (DMSO-d₆) δ1.27 (6H, s), 1.47 (6H, s), 1.55-1.86 (6H, m),1.90-2.10 (2H, m), 2.19 (2H, s), 2.90-3.10 (2H, m), 3.80-3.88 (2H, m),3.96 (3H, s), 4.37-(2H, br s), 7.60-7.82 (5H, m).

Example 121

[2217]6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenyl-5-[(1-piperidinyl)methyl]furo[2,3-h]isoquinoline

[2218] The title compound was obtained from3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenyl-5-[(1-piperidinyl)methyl]-6-furo[2,3-h]isoquinolinoland ethanol by the method similar to that in Example 114. Yield: 87%.

[2219] Melting point: 75-77° C. (ethyl acetate-hexane).

[2220]¹H NMR (CDCl₃) δ1.23 (6H, s), 1.26 (6H, s), 1.36 (3H, t, J=7.0Hz), 1.40-1.58 (6H, m), 2.12 (2H, s), 2.37-2.43 (4H, m), 2.82 (2H, s),3.49 (2H, s), 4.16 (2H, q, J=7.0 Hz), 7.35-7.42 (5H, m).

Example 122

[2221]3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-1-phenyl-5-[(1-piperidinyl)methyl]furo[2,3-h]isoquinolin-6-ylacetate dihydrochloride.

[2222] A free base of the title compound was obtained from3,4,8,9-tetrahydro-3,3,8-8-tetramethyl-1-phenyl-5-[(1-piperidinyl)methyl]-6-furo[2,3-h]isoquinolinolby the method similar to that in Example 118. This was converted into ahydrochloride with 4 M solution of hydrogen chloride/ethyl acetate, andthen concentrated under reduced pressure to obtain the title compound.Yield: 96%.

[2223] Amorphous.

[2224]¹H NMR (DMSO-d₆) δ1.22 (6H, s), 1.49 (6H, s), 1.61-1.82 (4H, m),1.93-2.45 (7H, m), 2.95-3.10 (2H, m), 3.38-3.64 (4H, m), 4.40-4.48 (2H,m), 7.60-7.83 (5H, m).

Example 123

[2225]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-(3-nitrophenyl)furo[2,3-h]isoquinoline

[2226] Conc. sulfuric acid (2.75 mL. 51.6 mmol) was added to a solutionof 2,3-dihydro-7-methoxy-2,2-dimethyl-5-(2-methyl-1-propenyl)benzofuran(6.00 g, 25.8 mmol), 3-nitrobenzonitrile (3.83 g, 25.8 mmol) and aceticacid (18 mL) in toluene (24 mL), and the mixture was stirred at 80° C.for 1 hour. The reaction solution was combined with excessive aqueousammonia, and extracted with ethyl acetate. The extract was washed withwater, and concentrated under reduced pressure. The residue wassubjected to a column chromatography on a basic silica gel (hexane/ethylacetate 17:3) to obtain the title compound (4.28 g, Yield: 44%).

[2227] Amorphous.

[2228]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.32 (6H, s), 2.19 (2H, s), 2.71(2H, s), 3.94 (3H, s), 6.65 (1H, s), 7.59 (1H, t, J=7.8 Hz), 7.73-7.79(1H, m), 8.22-8.32 (2H, m).

Example 124

[2229]3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-1-(3-nitrophenyl)-6-furo[2,3-h]isoquinolinol

[2230] Under nitrogen atmosphere, a mixture of3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-(3-nitrophenyl)furo[2,3-h]isoquinoline(4.20 g, 11.0 mmol) and hydrobromic acid (42 mL) was stirred at 100° C.for 20 hours. The reaction.solution was cooled, combined with aqueousammonia, and then extracted with ethyl acetate. The extract was washedwith water, and then concentrated under reduced pressure. The residuewas subjected to a column chromatography on a silica gel (hexane/ethylacetate 1:1), and recrystallized from ethyl acetate-hexane to obtain thetitle.compound (2.50 g, Yield: 62%).

[2231] Melting point: 239-241° C.

[2232]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.30 (6H, s), 2.18 (2H, s), 2.67(2H, s), 6.62 (1H, s), 7.58 (1H, t, J=7.8 Hz), 7.73-7.80 (1H, m),8.22-8.31 (2H, m).

Example 125

[2233]3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-1-(3-nitrophenyl)-5-[(1-piperidinyl)methyl]-6-furo[2,3-h]isoquinolinol

[2234] The title compound was obtained from3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-(3-nitrophenyl)-6-furo[2,3-h]isoquinolinoland piperidine by the method similar to that in Example 113. Yield: 78%.

[2235] Amorphous.

[2236]¹H NMR (CDCl₃) δ1.24 (6H, s), 1.31 (6H, s), 1.46-1.72 (6H, m),2.13 (2H, s), 2.40-2.80 (4H, m), 2.58 (2H, s), 3.78 (2H, s), 6.30 (1H,s), 7.56 (1H, t, J=8.0 Hz), 7.72-7.78 (1H, m), 8.22-8.31 (2H, m).

Example 126

[2237]6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-(3-nitrophenyl)-5-[(1-piperidinyl)methyl]furo[2,3-h]isoquinoline

[2238] The title compound was obtained from3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-(3-nitrophenyl)-5-[(1-piperidinyl)methyl]-6-furo[2,3-h]isoquinolinoland ethanol by the method similar to that in Example 114. Yield: 97%.

[2239] Amorphous.

[2240]¹H NMR (CDCl₃) δ1.24 (6H, s), 1.28 (6H, s), 1.37 (3H, t, J=7.0Hz), 1.40-1.60 (6H, m), 2.11 (2H, s), 2.36-2.44 (4H, m), 2.84 (2H, s),3.49 (2H, s), 4.18 (2H, q, J=7.0 Hz), 7.57 (1H, t, J=8.0 Hz), 7.78 (1H,d, J=8.0 Hz), 8.22-8.31 (2H, m).

Example 127

[2241]3-[6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-5-[(1-piperidinyl)methyl]furo[2,3-h]isoquinolin-1-yl]benzenamine

[2242] 20% aqueous solution of titanium trichloride (9.13 mL, 14.2 mmol)was added to a solution of6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-(3-nitrophenyl)-5-[(1-piperidinyl)methyl]furo[2,3-h]isoquinoline(1.00 g, 2.03 mmol) in acetic acid (5 mL) and the mixture was stirred atroom temperature for 30 minutes. The reaction solution was poured intoan excessive saturated aqueous solution of sodium hydrogen carbonate,and extracted with ethyl acetate. Tie extract was washed with water, andthen concentrated under reduced pressure to obtain the title compound(0.90 g, Yield: 96%).

[2243] Amorphous.

[2244]¹H NMR (CDCl₃) δ1.21 (6H, s), 1.28 (6H, s), 1.36 (3H, t, J=7.2Hz), 1.42-1.58 (6H, m), 2.27 (2H, s), 2.38-2.45 (2H, m), 2.80 (2H, s),3.48 (2H, s), 3.77 (2H, br s), 4.16 (2H, q, J=7.2 Hz), 6.66-6.76 (3H,m), 7.13 (1H, t, J=7.4 Hz).

Example 128

[2245]2-[[[3-[6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-5-[(1-piperidinyl)methyl]furo[2,3-h]isoquinolin-1-yl]phenyl]amino]carbonyl]benzoicacid

[2246] A solution of phthalic anhydride (0.314 g, 2.12 mmol) intetrahydrofuran (3 mL) was added to a solution of3-[6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-5-[(1-piperidinyl)methyl]furo[2,3-h]isoquinolin-1-yl]benzenamine(0.98 g, 2.12 mmol) in tetrahydrofuran (3 mL), and the mixture wasstirred at room temperature for 4 hours. The reaction solution wascombined with diisopropyl ether, and the precipitated crystals wererecovered by filtration and dried to obtain the title compound (1.20 g,Yield: 93%).

[2247] Melting point: 155-157° C.

[2248]¹H NMR (DMSO-d₆) δ1.13 (6H, s), 1.26 (6H, s), 1.28 (3H, t, J=7.0Hz), 1.40-1.60 (6H, m), 2.34 (2H, s), 2.42-2.56 (4H, m), 2.78 (2H, s),3.60 (2H, s), 4.12 (2H, q, J=7.0 Hz), 7.08 (1H, d, J=7.8 Hz), 7.36 (1H,t, J=7.8 Hz), 7.58-7.84 (7H, m), 10.77 (1H, br s).

Example 129

[2249]2-[3-[6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-5-[(1-piperidinyl)methyl]furo[2,3-h]isoquinolin-1-yl]phenyl]-1H-isoindole-1,3(2H)-dione

[2250] A mixture of2-[[[3-[6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-5-[(1-piperidinyl)methyl]furo[2,3-h]isoquinolin-1-yl]phenyl]amino]carbonyl]benzoicacid and acetic anhydride (5 mL) was stirred at 100° C. for 1 hour. Thereaction solution was combined with an excessive saturated aqueoussolution of sodium hydrogen carbonate, and extracted with ethyl acetate.The extract was washed with water, and then concentrated under reducedpressure. The residue was subjected to a column chromatography on asilica gel (ethyl acetate), and recrystallized from methanol-diisopropylether to obtain the title compound (0.50 g, Yield: 52%).

[2251] Melting point: 176-177° C.

[2252]¹H NMR (DMSO-d₆) δ1.18 (6H, br s), 1.23 (3H, t, J=7.0 Hz), 1.27(6H, s), 1.43 (6H, br s), 2.35 (4H, br s), 2.62-2.83 (4H, m), 3.42 (2H,s), 4.11 (2H, q, J=7.0 Hz), 7.38-7.40 (1H, m), 7.43-7.61 (3H, m),7.84-7.96 (4H, m).

Example 130

[2253]N-[3-[6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-5-[(1-piperidinyl)methyl]furo[2,3-h]isoquinolin-1-yl]phenyl]methanesulfonamide

[2254] Methanesulfonyl chloride (0.352 mL, 4.56 mmol) was added to asolution of3-[6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-5-[(1-piperidinyl)methyl]furo[2,3-h]isoquinolin-1-yl]benzenamine(0.70 g, 1.52mmol) in pyridine (4 mL) and the mixture was stirred atroom temperature for 3 hours. The reaction solution was combined with anexcessive saturated aqueous solution of sodium hydrogen carbonate, andextracted with ethyl acetate. The extract was washed with water, andthen concentrated under reduced pressure. The residue was recrystallizedfrom methanol-diisopropyl ether to obtain the title compound (0.52 g,Yield: 63%).

[2255] Melting point: 230-231° C.

[2256]¹H NMR (DMSO-d₆) δ1.12 (6H, s), 1.24 (6H, s), 1.28 (3H, t, J=7.0Hz), 1.42 (6H, br s), 2.22 (2H, s), 2.34 (4H, br s), 2.74 (2H, s), 2.99(3H, s), 3.44 (2H, br s), 4.09 (2H, q, J=7.0 Hz), 7.10-7.15 (2H, m),7.28-7.43 (2H, m), 9.72 (1H, br s).

Example 131

[2257]N-[3-[6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-5-[(1-piperidinyl)methyl]furo[2,3-h]isoquinolin-1-yl]phenyl]-N-(methylsulfonyl)methanesulfonamide

[2258] Methanesulfonyl chloride (0.184 mL, 2.38 mmol) was added to asolution ofN-[3-[6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-5-[(1-piperidinyl)methyl]furo[2,3-h]isoquinolin-1-yl]phenyl]methanesulfonamide(0.64 g, 1.19 mmol) and triethylamine (0.496 mL, 3.57 mmol) intetrahydrofuran (5 mL) and the mixture was heated under reflux for 20minutes. The reaction mixture was cooled, poured into a saturatedaqueous solution of sodium hydrogen carbonate, and then extracted withethyl acetate. The extract was washed with water, and then concentratedunder reduced pressure. The residue was subjected to a columnchromatography on a basic silica gel (hexane/ethyl acetate 2:1), andthen recrystallized from methanol-diisopropyl ether to obtain the titlecompound (0.45 g, Yield: 61%).

[2259] Melting point: 118-119° C.

[2260]¹H NMR (DMSO-d₆) δ1.10-1.31 (15H, m), 1.42 (6H, br s), 2.35 (4H,br s), 2.60-2.83 (4H, m), 3.43 (2H, s), 3.55 (6H, s), 4.08 (2H, q, J=7.0Hz), 7.42 (1H, s), 7.50-7.60 (3H, m).

Example 132

[2261]3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-5-(2-methylethyl)-1-phenyl-6-furo[2,3-h]isoquinolinol

[2262] A mixture of3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenyl-6-furo[2,3-h]isoquinolinol(0.30 g, 0.933 mmol), 2-propanol (0.357 mL, 4.67 mmol) and conc.sulfuric acid (0.995 mL, 18.7 mmol) was stirred at 55° C. for 1 hour.The reaction solution was poured into an excessive saturated aqueoussolution of sodium hydrogen carbonate, and extracted with ethyl acetate.The extract was washed with water, and then concentrated under reducedpressure. The residue was subjected to a column chromatography on abasic silica gel (hexane/ethyl acetate 3:1), and then recrystallizedfrom ethyl acetate-hexane to obtain the title compound (0.18 g, Yield:53%).

[2263] Amorphous.

[2264]¹H NMR (CDCl₃) δ1.24 (6H, s), 1.27 (6H, s), 1.38 (6H, d, J=7.2Hz), 2.15 (2H, s), 2.70 (2H, s), 3.25-3.46 (1H, m), 7.37 (5H, m).

Example 133

[2265]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-5-(1-methylethyl)-1-phenylfuro[2,3-h]isoquinolinehydrochloride

[2266] A free base of the title compound was obtained as an oil from3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-5-(1-methylethyl)-1-phenyl-6-furo[2,3-h]isoquinolinolby the method similar to that in Example 114. Yield: 69%. This free basewas converted into a hydrochloride with 4 M solution of hydrogenchloride/ethyl acetate, and then concentrated under reduced pressure toobtain the title compound. Yield: 65%.

[2267] Amorphous.

[2268]¹H NMR (DMSO-d₆) δ1.25 (6H, s), 1.30 (6H, d, J=7.0 Hz), 1.45 (6H,s), 2.12 (2H, s), 3.17 (2Hz s), 3.23-3.45 (1H, m), 3.97 (3H, s),7.52-7.78 (5H, m).

Example 134

[2269]6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-5-(1-methylethyl)-1-phenylfuro[2,3-h]isoquinolinehydrochloride

[2270] A free base of the title compound was obtained as an oil from3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-5-(1-methylethyl)-1-phenyl-6-furo[2,3-h]isoquinolinoland ethanol by the method similar to that in Example 114. Yield: 40%.This free base was converted into a hydrochloride with 4 M solution ofhydrogen chloride/ethyl acetate, and then concentrated under reducedpressure to obtain the title compound. Yield: 39%.

[2271] Amorphous.

[2272]¹H NMR (DMSO-d₆) δ1.23 (6H, s), 1.32 (6H, d, J=7.0 Hz), 1.34 (3H,t, J=7.0 Hz), 1.45 (6H, s), 2.11 (2H, s), 3.17 (2H, s), 3.31-3.46 (1H,m), 4.33 (2H, q, J=7.0 Hz), 7.52-7.78 (5H, m).

Example 135

[2273]3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-5-(1-methylethyl)-1-phenylfuro[2,3-h]isoquinolin-6-ylacetate hydrochloride

[2274] A free base of the title compound was obtained as an oil from3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-5-(1-methylethyl)-1-phenyl-6-furo[2,3-h]isoquinolinolby the method similar to that in Example 118. Yield: 93%. This wasconverted into a hydrochloride with 4 M solution of hydrogenchloride/ethyl acetate, and then concentrated under reduced pressure toobtain the title compound. Yield: 87%.

[2275] Amorphous.

[2276]¹H NMR (DMSO-d₆) δ1.19 (6H, s), 1.26 (6H, d, J=7.0 Hz), 1.48 (6H,s), 2.17 (2H, s), 2.35 (3H, s), 3.23 (2H, s), 3.35 (1H, septet, J=7.0Hz), 7.60-7.80 (5H, m).

Example 136

[2277]3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-6-[(2-methyl-2-propenyl)oxy]-1-phenylfuro[2,3-h]isoquinolinehydrochloride

[2278] Under nitrogen atmosphere, a suspension of3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenyl-6-furo[2,3-h]isoquinolinol(0.80 g, 2.49 mmol), 3-chloro-2-methyl-1-propene (0.258 mL, 2.61 mmol)and potassium carbonate (0.361 g, 2.61 mmol) in N,N-dimethylformamide (4mL) was stirred at 80° C. for 2 hours. The reaction mixture was combinedwith water and extracted with ethyl acetate. The extract was washed withwater, and then concentrated under reduced pressure. The residue wassubjected to a column chromatography on a basic silica gel (hexane/ethylacetate 9:1) to obtain a free base (0.93 g, quantitative) of the titlecompound as an oil. An aliquot was converted into a hydrochloride saltwith 4 M solution of hydrogen chloride/ethyl acetate, and thenconcentrated under reduced pressure to obtain the title compound.

[2279] Amorphous.

[2280]¹H NMR (DMSO-d₆) δ1.23 (6H, s), 1.46 (6H, s), 1.78 (3H, s), 2.17(2H, s), 3.15 (2H, s), 4.70 (2H, s), 5.02 (1H, s), 5.08 (1H, s), 7.11(1H, s), 7.61-7.80 (5H, m).

Example 137

[2281]3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-5-(2-methyl-2-propenyl)-1-phenyl-6-furo[2,3-h]isoquinolinol

[2282] Under nitrogen atmosphere, a solution of3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-6-[(2-methyl-2-propenyl)oxy]-1-phenylfuro[2,3-h]isoquinoline(0.78 g, 2.08 mmol) in N,N-diethylaniline (4 mL) was stirred at 205° C.for 4.5 hours. The reaction solution was cooled, and then combined withhexane, and the precipitated crystals were recovered by filtration.Recrystallization from ethyl acetate-hexane gave the title compound(0.41 g, Yield: 53%).

[2283] Melting point: 196-198° C.

[2284]¹H NMR (CDCl₃) δ1.22 (6H, s), 1.28 (6H, s), 1.84 (3H, s), 2.17(2H, s), 2.59 (2H, s), 3.37 (2H, s), 4.51 (1H, s), 4.80 (1H, s), 7.37(5H, s).

Example 138

[2285]3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-1-phenyl-6-[(2-propynyl)oxy]furo[2,3-h]isoquinolinehydrochloride

[2286] Under nitrogen atmosphere, a mixture of3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenyl-6-furo[2,3-h]isoquinolinol(1.00 g, 3.11 mmol), propargyl bromide (0.305 mL, 3.42 mmol), potassiumcarbonate (0.473 g, 3.42 mmol) and N,N-dimethylformamide (10 mL) wasstirred at 60° C. for 2 hours. The reaction mixture was combined withwater, and extracted with ethyl acetate. The extract was washed withwater, and then concentrated under reduced pressure. The residue wassubjected to a column chromatography on a silica gel (hexane/ethylacetate 1:1) to obtain a free base (1.11 g, quantitative) of the titlecompound as an oil.

[2287]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.30 (6H, s), 2.19 (2H, s), 2.55(1H, t, J=2.4 Hz), 2.70 (2H, s), 4.83 (2H, d, J=2.4 Hz), 6.77 (1H, s),7.39 (5H, s).

[2288] An aliquot was converted into a hydrochloride salt with 4 Msolution of hydrogen chloride/ethyl acetate, and then concentrated underreduced pressure to obtain the title compound.

[2289] Amorphous.

[2290]¹H NMR (DMSO-d₆) δ1.23 (6H, s), 1.46 (6H, s), 2.18 (2H, s), 3.17(2H, s), 3.76 (1H, s), 5.02 (2H, s), 7.14 (1H, s), 7.62-7.80 (5H, m).

Example 139

[2291]4-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoylchloride hydrochloride

[2292] A mixture of4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid hydrochloride (0.30 g, 0.721 mmol) and thionyl chloride (1 mL) wasstirred at 70° C. for 1 hour. The reaction solution was concentratedunder reduced pressure to obtain the title compound (0.30 g, Yield:96%). This was used in the next reaction without further purification.

Example 140

[2293]3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoylchloride hydrochloride

[2294] The title compound was obtained as an amorphous material using3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid hydrochloride by the method similar to that in Example 139. Yield:96%. This compound was used in the next reaction without furtherpurification.

Example 141

[2295]N-(4-Pyridinyl)-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamidedihydrochloride

[2296]4-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoylchloride hydrochloride (0.30 g, 0.691 mmol) was added to a solution of4-aminopyridine (71.5 mg, 0.760 mmol) and triethylamine (0.116 mL, 0.829mmol) in N,N-dimethylformamide (1 mL) with cooling in ice, and themixture was stirred at room temperature for 1 hour. The reaction mixturewas combined with a saturated aqueous solution of sodium hydrogencarbonate, and extracted with ethyl acetate. The extract was washed withwater, and then concentrated under reduced pressure. The residue wassubjected to a column chromatography on a silica gel (ethylacetate/methanol 19:1) to obtain a free base (0.31 g, Yield: 98%) of thetitle compound as an oil. This was converted into a hydrochloridesalt.with 4 M solution of hydrogen chloride/ethyl acetate, concentratedunder reduced pressure, and then recrystallized from methanol-ethylacetate to obtain the title compound (0.29 g, Yield: 74%).

[2297] Melting point: 194-198° C.

[2298]¹H NMR (DMSO-d₆) δ1.24 (6H, s), 1.49 (6H, s), 2.22 (2H, s), 3.20(2H, s), 3.96 (3H, s), 7.13 (1H, s), 7.84 (2H, d, J=8.0 Hz), 8.45 (2H,d, J=8.0 Hz), 8.63 (2H, d, J=7.0 Hz), 8.82 (2H, d, J=7.0 Hz), 12.55 (1H,s).

Example 142

[2299]N-(3-Pyridinyl)-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamidedihydrochloride

[2300] The title compound was obtained using 3-aminopyridine by themethod similar. to that in Example 141. Yield: 85%.

[2301] Amorphous.

[2302]¹H NMR (DMSO-d₆) δ1.24 (6H, s), 1.49 (6H, s), 2.23 (2H, s), 3.20(2H, s), 3.96 (3H, s), 7.14 (1H, s), 7.84 (2H, d, J=8.0 Hz), 8.08-8.17(1H, m), 8.46 (2H, d, J=8.0 Hz), 8.71 (1H, d, J=5.4 Hz), 9.10 (1H, d,J=7.6 Hz), 9.56 (1H, s), 12.15 (1H, s).

Example 143

[2303]N-(2-Pyridinyl)-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamidedihydrochloride

[2304] The title compound was obtained using 2-aminopyridine by themethod similar to that in Example 141. Yield: 74%.

[2305] Amorphous.

[2306]¹H NMR (DMSO-d₆) δ1.24 (6H, s), 1.49 (6H, s), 2.22 (2H, s), 3.20(2H, s), 3.96 (3H, s), 7.13 (1H, s), 7.38-7.46 (1H, m), 7.83 (2H, d,J=7.8 Hz), 7.91-7.99 (1H, m), 8.12-8.20 (1H, m), 8.37 (2H, d, J=7.8 Hz),8.53 (1H, d, J=4.4 Hz), 12.04 (1H, s).

Example 144

[2307]N-(4-Pyridinylmethyl)-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamidedihydrochloride

[2308] The title compound was obtained using 4-(aminomethyl)pyridine bythe method similar to that in Example 141. Yield: 75%.

[2309] Melting point: 220-225° C. (methanol-ethyl acetate).

[2310]¹H NMR (DMSO-d₆) δ1.24 (6H, s), 1.48 (6H, s), 2.22 (2H, s), 3.19(2H, s), 3.95 (3H, s), 4.77 (2H, d, J=5.4 Hz), 7.13 (1H, s), 7.78 (2H,d, J=8.4 Hz), 7.98 (2H, d, J=6.2 Hz), 8.23 (2H, d, J=8.4 Hz), 8.87 (2H,d, J=6.2 Hz), 9.96-10.03 (1H,

Example 145

[2311]N-(3-Pyridinylmethyl)-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamidedihydrochloride

[2312] The title compound was obtained using 3-(aminomethyl)pyridine bythe method similar to that in Example 141. Quantitative.

[2313] Amorphous.

[2314]¹H NMR (DMSO-d₆) δ1.23 (6H, s), 1.47 (6H, s), 2.22 (2H, s), 3.18(2H, s), 3.95 (3H, s), 4.70 (2H, d, J=4.0 Hz), 7.12 (1H, s), 7.77 (2H,d, J=8.0 Hz), 8.01-8.08 (1H, m), 8.22 (2H, d, J =8.0 Hz), 8.58 (1H, d,J=7.4 Hz), 8.85 (1H, d, J=5.2 Hz), 8.95 (1H, s), 9.95-10.04 (1H, m).

Example 146

[2315]N-(2-Pyridinylmethyl)-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamidedihydrochloride

[2316] The title. compound was obtained using 2-(aminomethyl)pyridine bythe method similar to that in Example 141. Yield: 75%.

[2317] Amorphous.

[2318]¹H NMR (DMSO-d₆) δ1.24 (6H, s), 1.48 (6H, s), 2.21 (2H, s), 3.19(2H, s), 3.95 (3H, s), 4.90 (2H, s), 7.13 (1H, s), 7.78 (2H, d, J=7.2Hz), 7.90-8.04 (2H, m), 8.24 (2H, d, J=7.2 Hz), 8.46-8.55 (1H, m), 8.85(1H, d, J=4.8 Hz), 10.05 (1H, s).

Example 147

[2319]N-[2-(4-Pyridinyl)ethyl]-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamidedihydrochloride

[2320] The title compound was obtained using 4-(2-aminoethyl)pyridine bythe method similar to that in Example 141. Yield: 83%.

[2321] Amorphous.

[2322]¹H NMR (DMSO-d₆) δ1.23 (6H, s), 1.47 (6H, s), 2.18 (2H, s),3.16-3.27 (4H, m), 3.65-3.76 (2H, m), 3.95 (3H, s), 7.12 (1H, s), 7.72(2H, d, J=7.6 Hz), 7.96-8.12 (4H, m), 8.84 (2H, d, J =5.6 Hz), 9.25 (1H,br s).

Example 148

[2323]N-(4-Pyridinylmethyl)-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide

[2324]3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoylchloride hydrochloride (0.50 g, 1.15 mmol) was added to a solution of4-(aminomethyl)pyridine (0.129 mL, 1.27 mmol) and triethylamine (0.193mL, 1.38 mmol) in N,N-dimethylformamide (5 mL) with cooling in ice, andthe mixture was stirred with cooling in ice for 30 minutes. The reactionmixture was combined with a saturated aqueous solution of sodiumhydrogen carbonate, and extracted with ethyl acetate. The extract waswashed with water, and then concentrated under reduced pressure. Theresidue was recrystallized from ethyl acetate-diisopropyl ether toobtain the title compound (0.32 g, Yield: 59%).

[2325] Melting point: 197-198° C.

[2326]¹H NMR (CDCl₃) δ1.19 (6H, s), 1.30 (6H, s), 2.18 (2H, s), 2.63(2H, s), 3.93 (3H, s), 4.59 (2H, d, J=6.0 Hz), 6.61 (1H, s), 7.19 (2H,d, J=5.8 Hz), 7.41-7.53 (3H, m), 7.93-8.01 (2H, m), 8.51-8.56 (2H, m).

Example 149

[2327]N-[2-(4-Pyridinyl)ethyl]-3-(3,4.8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide

[2328] The title compound was obtained using 4-(2-aminoethyl)pyridine bythe method similar to that in Example 148. Yield:68%.

[2329] Melting point: 144-145° C. (ethyl acetate-diisopropyl ether).

[2330]¹H NMR (CDCl₃) δ1.24 (6H, s), 1.30 (6H, s), 2.17 (2H, s), 2.68(2H, s), 2.91 (2H, t, J=7.2 Hz), 3.70 (2H, q, J=7.2 Hz), 3.93 (3H, s),6.62 (1H, s), 6.65 (1H, br s), 7.17 (2H, d, J=6.2 Hz), 7.41-7.50 (2H,m), 7.79 (1H, s), 7.81-7.87 (1H, m), 8.51 (2H, d, J=6.2 Hz).

Example 150

[2331]N-(2-Pyrimidinyl)-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamidedihydrochloride

[2332]4-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoyl chloride hydrochloride (0.30 g, 0.691 mmol) was added to asolution of 2-aminopyrimidine (72.3 mg, 0.760 mol) in pyridine (3 mL),and the mixture was stirred at room temperature for 2 hours. Thereaction solution was combined with a saturated aqueous solution ofsodium hydrogen carbonate, and extracted with ethyl acetate. The extractwas washed with water, and then concentrated under reduced pressure. Theresidue was converted into a hydrochloride salt with 4 M solution ofhydrogen chloride/ethyl acetate, and then concentrated under reducedpressure to obtain the title compound (0.29 g, Yield: 79%).

[2333] Amorphous.

[2334]¹H NMR (DMSO-d₆) δ1.24 (6H, s), 1.48 (6H, s), 2.18 (2H, s), 3.20(2H, s), 3.97 (3H, s), 7.11 (1H, s), 7.38-7.51 (1H, m), 7.83 (2H, d,J=8.0 Hz), 8.50 (2H, d, J=8.0 Hz), 8.92-9.98 (2H, m), 11.82 (1H, br s).

Example 151

[2335] N-Pyrazinyl-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide

[2336]4-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoylchloride hydrochloride (0.30 g, 0.691 mmol) was added to a solution ofaminopyrazine (72.3 mg, 0.760 mmol) in pyridine (3 mL) and the mixturewas stirred at room temperature for 5 hours. The reaction solution wascombined with a saturated aqueous solution of sodium hydrogen carbonate,and extracted with ethyl acetate. The extract was washed with water, andthen concentrated under reduced pressure. The residue was subjected to acolumn chromatography on a basic silicas gel (ethyl acetate/methanol19:1) to obtain the title compound (0.27 g, Yield: 86%).

[2337] Amorphous.

[2338]¹H NMR (DMSO-d₆) δ1.27 (6H, s), 1.32 (6H, s), 2.21 (2H, s), 2.72(2H, s), 3.93 (3H, s), 6.64 (1H, s), 7.58 (2H, d, J=8.4 Hz), 7.99 (2H,d, J=8.4 Hz), 8.27-8.33 (1H, m), 8.42 (1H, d, J=2.6 Hz), 8.61 (1H, brs), 9.75 (1H, d, J=1.6 Hz).

Example 152

[2339]N-(6-Chloro-3-pyridazinyl)-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide

[2340] The title compound was obtained using 3-amino-6-chloropyridazineby the method similar to that in Example 151. Yield: 85%.

[2341] Amorphous.

[2342]¹H NMR (DMSO-d₆) δ1.27 (6H, s), 1.33 (6H, s), 2.21 (2H, s), 2.71(2H, s), 3.93 (3H, s), 6.64 (1H, s), 6.74 (1H, d, J=9.2 Hz), 7.25 (1H,d, J=9.2 Hz), 7.59 (2H, d, J=8.4 Hz), 8.00 (2H, d, J=8.4 Hz), 9.18 (1H,br 5).

Example 153

[2343]N-(4-Pyridinyl)-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide

[2344]3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoylchloride hydrochloride (0.50 g, 1.15 mmol) was added to a solution of4-aminopyridine (0.119 g, 1.27 mmol) in pyridine (5 mL) and the mixturewas stirred at 50° C. for 1 hour. The reaction solution was combinedwith a saturated aqueous solution of sodium hydrogen carbonate, andextracted with ethyl acetate. The extract was washed with water, andthen concentrated under reduced pressure. The residue was recrystallizedfrom ethyl acetate-diisopropyl ether to obtain the title compound (0.25g, Yield: 48%).

[2345] Melting point: 175-176° C.

[2346]¹H NMR (CDCl₃) δ1.27 (6H, s), 1.31 (6H, s), 2.22 (2H, s), 2.71(2H, s), 3.93 (3H, s), 6.64 (1H, s), 7.48-7.58 (2H, m), 7.72-7.88 (2H,m), 8.00-8.06 (2H, m), 8.48-8.54 (2H, m), 9.71 (1H, br s).

Example 154

[2347]N-(3,5-Dichloro-4-pyridinyl)-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide

[2348] A mixture of3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid hydrochloride (2.17 g, 5.22 mmol) and thionyl chloride (2 mL) wasstirred at 70° C. for 1 hour. The reaction solution was concentratedunder reduced pressure, and the residue was combined with toluene, andconcentrated under reduced pressure again. A solution of4-Amino-3,5-dichloropyridine (0.50 g, 3.07 mmol) inN,N-dimethylformamide (10 mL) was cooled with ice and sodium hydride(66% suspension in oil) (0.379 g, 10.4 mmol) was added to the solution.And then, the acid chloride which had been previously prepared was addedthereto. The mixture was stirred at room temperature for 30 minutes,poured into ice water, and then extracted with ethyl acetate. Theextract was washed with water, and then concentrated under reducedpressure. The residue was subjected to a column chromatography on abasic silica gel (ethyl acetate) to obtain the title compound (0.35 g,Yield: 22%).

[2349] Melting point: 227-228° C.

[2350]¹H NMR (CDCl₃) δ1.21 (6H, s), 1.32 (6H, s), 2.23 (2H, s), 2.66(2H, s), 3.93 (3H, s), 6.63 (1H, s), 7.52 (1H, t, J=7.8 Hz), 7.69 (1H,t, J=7.8 Hz), 8.00-8.06 (2H, m), 8.57 (2H, s), 9.02 (1H, br s).

Example 155

[2351]N-[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoyl]glycineethyl ester hydrochloride

[2352] Triethylamine (5.86 mL, 42.0 mmol) was added to a solution of3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid hydrochloride (5.00 g, 12.0 mmol), glycine ethyl esterhydrochloride (1.85 g, 13.2 mmol) and 1-hydroxy-1H-benzotriazolemonohydrate (2.03 g, 13.2 mmol) in N,N-dimethylformamide (30 mL). Andthen, 1-ethyl-3-(3-dimethylaminopropyl)carbodimide hydrochloride (3.00g, 15.6 mmol),was added thereto. The mixture was stirred at roomtemperature for 5 hours, and then poured into a saturated aqueoussolution of sodium hydrogen carbonate. This was extracted with ethylacetate, and then the extract was washed with water, and concentratedunder reduced pressure. The residue was subjected to a columnchromatography on a basic silica gel (hexane/ethyl acetate 1:1) toobtain a free base (5.05 g, Yield: 94%) of the title-compound.

[2353]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.30 (3H, t, J=7.2 Hz), 1.31 (6H,s), 2.17 (2H, s), 2.69 (2H, s), 3.93 (3H, s), 4.21-4.30 (4H, m), 6.62(1H, s), 6.89-6.95 (1H, m), 7.42-7.55 (2H, m), 7.83-7.91 (2H, m).

[2354] An aliquot was converted into a hydrochloride salt with 4 Msolution of hydrogen chloride/ethyl acetate, and then concentrated underreduced pressure to obtain the title compound.

[2355] Amorphous.

[2356]¹H NMR (DMSO-d₆) δ1.21 (6H, s), 1.22 (3H, t, J=7.8 Hz), 1.47 (6H,s), 2.19 (2H, s), 2.78 (2H, s), 3.95 (3H, s), 4.03 (2H, t, J=6.2 Hz),4.12 (2H, q, J=7.8 Hz), 7.12 (1H, s), 7.75-7.83 (2H, m), 8.16 (1H, s),8.22-8.29 (1H, m), 9.28-9.35 (1H, m).

Example 156

[2357]N-[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoyl]glycinehydrochloride

[2358] 5 M aqueous solution of sodium hydroxide (5 mL) was added to asolution ofN-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoyl]glycineethyl ester (5.00 g, 11.1 mmol) in ethanol (20 mL) and the mixture wasstirred at room temperature for 1 hour. 5 M hydrochloric acid (7.5 mL)was added to the reaction mixture and the mixture was concentrated underreduced pressure. The residue was combined with ethanol and filtered,and the filtrate was concentrated under reduced pressure, and thisprocedure was repeated 3 times. The residue was combined withdiisopropyl ether, and a precipitate was recovered by filtration anddried to obtain the title compound (5.15 g, Yield: 98%).

[2359] Amorphous.

[2360]¹H NMR (DMSO-d₆) δ1.23 (6H, s), 1.47 (6H, s), 2.21 (2H, s), 3.18(2H, s), 3.95 (3H, s), 3.96-4.06 (2H, m), 7.12 (1H, s), 7.70-7.82 (2H,m), 8.18-8.28 (2H, m), 9.20-9.28 (1H, m).

Example 157

[2361]N-(2-Amino-2-oxoethyl)-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide

[2362] 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(0.422 g, 2.20 mmol) was added to a solution ofN-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoyl]glycinehydrochloride (0.80 g, 1.69 mmol) and 1-hydroxy-1H-benzotriazolemonohydrate (0.285 g, 1.86 mmol) in N,N-dimethylformamide (4 mL) and themixture was stirred at room temperature for 5 hours. Conc. aqueousammonia (1.7 mL) was added thereto, and the mixture was stirred at roomtemperature further for 1.5 hours. The reaction solution was combinedwith water, and extracted with ethyl acetate. The extract was washedwith water, and then concentrated under reduced pressure. The residuewas subjected to a column chromatography on a basic silica gel (ethylacetate followed by ethyl acetate/methanol 19:1) to obtain the titlecompound (0.43 g, Yield: 58%). An aliquot was recrystallized from ethylacetate-diisopropyl ether.

[2363] Melting point: 141-142° C.

[2364]¹H NMR (CDCl₃) δ1.23 (6H, s), 1.30 (6H, s), 2.16 (2H, s), 2.67(2H, s), 3.93 (3H, s), 4.08 (2H, d, J=5.0 Hz), 5.72 (1H, br s), 6.33(1H, br s), 6.62 (1H, s), 7.43-7.55 (2H, m), 7.62-7.70 (1H, m),7.89-7.99 (2H, m).

Example 158

[2365]N-[2-(Methylamino)-2-oxoethyl]-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide

[2366] The title compound was obtained using a 40% solution ofmethylamine/methanol by the method similar to that in Example 157.Yield: 40%.

[2367] Melting point: 212-213° C. (ethyl acetate-hexane).

[2368]¹H NMR (CDCl₃) δ1.23 (6H, s), 1.30 (6H, s), 2.16 (2H, s), 2.68(2H, s), 2.83 (3H, d, J=4.8 Hz), 3.93 (3H, s), 4.05 (2H, d, J =4.8 Hz),6.21 (1H, br s), 6.62 (1H, s), 7.42-7.55 (3H, m), 7.88-7.96 (2H, m).

Example 159

[2369]N-[2-Oxo-2-(phenylamino)ethyl]-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide

[2370] Triethylamine (0.707 mL, 5.07 mmol) and.aniline (0.170 mL, 1.86mmol) were added to a solution ofN-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoyl]glycinehydrochloride (0.80 g, 1.69 mmol) and 1-hydroxy-1H-benzotriazolemonohydrate (0.285 g, 1.86 mmol) in N,N-dimethylformamide (4 mL). Andthen, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(0.422g, 2.20 mmol) was added thereto and the mixture was stirred atroom temperature for 2 hours. The reaction mixture was combined with asaturated aqueous solution of sodium hydrogen carbonate, and extractedwith ethyl acetate. The extract was washed with water, and thenconcentrated under reduced pressure. The residue was subjected to acolumn chromatography on a basic silica gel (hexane/ethyl acetate 1:1followed by ethyl acetate/methanol 19:1) to obtain the title compound(0.30 g, Yield:35%).

[2371] Amorphous.

[2372]¹H NMR (DMSO-d₆) δ1.23 (6H, s), 1.27 (6H, s), 2.14 (2H, s), 2.65(2H, s), 3.93 (3H, s) 4.21 (2H, d, J=5.6 Hz), 6.62 (1H, s), 7.10 (1H, t,J=7.6 Hz), 7.26-7.41 (3H, m), 7.46-7.57 (3H, m), 7.87-7.94 (2H, m),8.06-8.15 (1H, m), 8.90 (1H, s).

Example 160

[2373]N-[2-Oxo-2-[(4-pyridinylmethyl)amino]ethyl]-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide

[2374] The title compound was obtained.using 4-(aminomethyl)pyridine bythe method similar to that in Example 159. Yield: 62%.

[2375] Melting point: 197-198° C. (ethyl acetate-diisopropyl ether).

[2376]¹H NMR (CDCl₃) δ1.22 (6H, s), 1.29 (6H, s), 2.16 (2H, s), 2.67(2H, s), 3.93 (3H, s), 4.12 (2H, d, J=5.4 Hz), 4.43 (2H, d, J =6.0 Hz),6.62 (1H, s), 7.11-7.19 (3H, m), 7.41-7.50 (2H, m), 7.65-7.71 (1H, m),7.84-7.91 (1H, m), 7.97 (1H, s), 8.48-8.55 (2H, m).

Example 161

[2377]N-(2-Oxo-2-[[2-(4-pyridinyl)ethyl]amino]ethyl1-3-[3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]benzamide

[2378] The title compound was obtained using 4-(2-aminoethyl)pyridine bythe method similar to that in Example 159. Yield: 82%.

[2379] Amorphous.

[2380]¹H NMR (CDCl₃) δ1.20 (6H, s), 1.30 (6H, s), 2.17 (2H, s), 2.66(2H, s), 2.81 (2H, t, J=6.0 Hz), 3.52 (2H, q, J=6.0 Hz), 3.92 (3H, s),3.97 (2H, d, J=5.4 Hz), 6.61 (1H, s), 6.72-6.78 (1H, m), 7.10 (2H, d,J=6.2 Hz), 7.41-7.50 (2H, m), 7.76-7.81 (1H, m), 7.88-7.94 (1H, m), 7.98(1H, s), 8.41-8.47 (2H, m).

Example 162

[2381]N-[2-(3-pyridinyl)ethyl]-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide

[2382] The title compound was obtained from3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[23-h]isoqulnoline-1-yl)benzoic acid hydrochloride and3-(2-aminoethyl)pyridine by the method similar to that in Example 159.Yield: 88%.

[2383] Amorphous.

[2384]¹H NMR (CDCl₃) δ1.24 (6H, s), 1.30 (6H, s), 2.18 (2H, s), 2.68(2H, s), 2.87-2.96 (2H, m), 3.69 (2H, q, J=6.6 Hz), 3.93 (3H, s), 6.62(1H, s), 6.71 (1H, br s), 7.21-7.28 (1H, m), 7.43-7.48 (2H, m),7.58-7.62 (1H, m), 7.80-7.86 (2H, m), 8.48-8.50 (2H, m).

Example 163

[2385]N-[2-(2-Pyridinyl)ethyl]-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide

[2386] The title compound was obtained from3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid hydrochloride and 2-(2-aminoethyl)pyridine by the method similar tothat in Example 159. Yield: 71%.

[2387] Amorphous.

[2388]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.27 (6H, s), 2.17 (2H, s), 2.70(2H, s), 3.09 (2H, t, J=6.2 Hz), 3.85 (2H, q, J=6.2 Hz), 3.94 (3H, s),6.64 (1H, s), 7.10-7.22 (2H, m), 7.40-7.51 (2H, m), 7.58-7.70 (2H, m),7.80 (1H, m), 7.84-7.90 (1H, m), 8.42 (1H, d, J=4.4 Hz).

Example 164

[2389]N-[3-(4-Pyridinyl)propyl]-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide

[2390] The title compound was obtained from3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid hydrochloride and 4-(3-aminopropyl)pyridine by the method similarto that in Example 159. Yield: 63%.

[2391] Melting point: 175-176° C. (ethyl acetate-diisopropyl ether).

[2392]¹H NMR (CDCl₃) δ1.23 (6H, s), 1.29 (6H, s), 1.82-1.99 (2H, m),2.16 (2H, s), 2.62-2.72 (4H, m), 3.41-3.50 (2H, m), 3.92 (3H, s),6.60-6.65 (1H, m), 7.13 (2H, d, J=6.0 Hz), 7.43-7.46 (2H, m), 7.83-7.90(2H, m), 8.50 (2H, d, J=6.0 Hz).

Example 165

[2393]N-[3-(3-Pyridinyl)propyl]-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide

[2394] The title compound was obtained from3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid hydrochloride and 3-(3-aminopropyl)pyridine by the method similarto that in Example 159. Yield: 55%.

[2395] Melting point: 161-162° C. (ethyl acetate-diisopropyl ether).

[2396]¹H NMR (CDCl₃) δ1.21 (6H, s), 1.29 (6H, s), 1.79-1.95 (2H, m),2.14-2.18 (2H, m), 2.60-2.69 (4H, m), 3.38-3.49 (2H, m), 3.92 (3H, s),6.61 (1H, s), 6.81-6.90 (1H, m), 7.18-7.24 (1H, m), 7.41-7.55 (3H, m),7.86-7.93 (2H, m), 8.42-8.47 (2H, m).

Example 166

[2397]N-[3-(1H-Imidazol-1-yl)propyl]-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide

[2398] The title compound was obtained from3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid hydrochloride and 1-(3-aminopropyl)imidazole by the method similarto that in Example 159. Yield: 70%.

[2399] Melting point: 104-106° C. (ethyl acetate-hexane).

[2400]¹H NMR (CDCl₃) δ1.22 (6H, s), 1.30 (6H, s), 2.04 (2H, quintet,J=7.0 Hz), 2.18 (2H, s), 2.68 (2H, s), 3.36-3.47 (2H, m), 3.93 (3H, s),4.01 (2H, t, J=7.0 Hz), 6.62 (1H, s), 6.90-6.97 (2H, m), 7.05 (1H, s),7.44-7.50 (3H, m), 7.85-7.90 (2H, m).

Example 167

[2401]N-[2-[4-(Aminosulfonyl)phenyl]ethyl]-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide

[2402] The title compound was obtained from3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid hydrochloride and 4-(2-aminoethyl)benzenesulfonamide by the methodsimilar to that in Example 159. Yield: 85%.

[2403] Melting point: 138-139° C. (ethyl acetate-diisopropyl ether).

[2404]¹H NMR (CDCl₃) δ1.21 (6H, s), 1.28 (6H, s), 2.15 (2H, s), 2.68(2H, s), 2.91-2.98 (2H, m), 3.63-3.75 (2H, m), 3.93 (3H, s), 5.22 (2H,br s), 6.62 (1H, s), 6.78-6.84 (1H, m), 7.33 (2H, d, J=8.0 Hz), 7.46(2H, d, J=4.8 Hz), 7.73-7.80 (3H, m), 7.83-7.89 (1H, m).

Example 168

[2405]N-(Hexahydro-2-oxo-1H-azepin-3-yl)-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide

[2406] The title compound was obtained from3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid hydrochloride and 3-aminohexahydro-2-azepinone by the methodsimilar to that in Example 159. Yield: 65%.

[2407] Melting point: 187-188° C. (ethyl acetate-hexane).

[2408]¹H NMR (CDCl₃) δ1.25 (3H, s), 1.27 (3H, s), 1.30 (6H, s),1.50-2.25 (6H, m), 2.16 (2H, s), 2.70 (2H, s), 3.18-3.40 (2H, m), 3.93(3H, s), 4.68-4.77 (1H, m), 6.41 (1H, br s), 6.62 (1H, s), 7.41-7.49(2H, m), 7.75-7.80 (1H, m), 7.88-7.96 (2H, m).

Example 169

[2409]N-(Hexahydro-5-oxo-1,4-thiazepin-6-yl)-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide

[2410] The title compound was obtained from3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid hydrochloride and 6-amino-1,4-thiazepin-5-one by the method similarto that in Example 159. Yield: 51%.

[2411] Melting point: 206-207° C. (ethyl acetate-diisopropyl ether).

[2412]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.29 (6H, s),2.14 (2H, s), 2.50-2.89(3H, m), 2.71 (2H, s), 2.87-2.97 (1H, m), 3.58-3.83 (2H, m), 3.93 (3H,s), 5.05-5.13 (1H, m), 6.62 (1H, s), 6.80-6.88 (1H, m), 7.45-7.50 (2H,m), 7.89-7.96 (3H, m).

Example 170

[2413]N-[2-(4-Pyridinylamino)ethyl]-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide

[2414] The title compound was obtained from3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid hydrochloride and 4-[(2-aminoethyl)amino]pyridine by the methodsimilar to that in Example 159. Yield: 53%.

[2415] Amorphous.

[2416]¹H NMR (CDCl₃) δ1.22 (6H, s), 1.29 (6H, s), 2.17 (2H, s), 2.66(2H, s), 3.30-3.39 (2H, m), 3.60-3.70 (2H, m), 3.92 (3H, s), 5.12-5.18(1H, m), 6.44 (2H, d, J=5.2 Hz), 6.62 (1H, s), 7.38-7.44 (3H, m),7.82-7.90 (2H, m), 8.14 (2H, d, J=5.2 Hz).

Example 171

[2417]N-[2-(2-Pyridinylamino)ethyl]-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide

[2418] The title compound was obtained from3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid hydrochloride and 2-[(2-aminoethyl)amino]pyridine by the methodsimilar to that in Example 159. Yield: 33%.

[2419] Amorphous.

[2420]¹H NMR (CDCl₃) δ1.27 (12H, s), 2.14 (2H, s), 2.71 (2H, s), 3.63(4H, s), 3.93 (3H, s), 4.91 (1H, br s), 6.40-6.52 (2H, m), 6.64 (1H, s),7.29-7.39 (1H, m), 7.43-7.48 (2H, m), 7.84 (1H, s), 7.90-7.99 (2H, m),8.49 (1H, br s).

Example 172

[2421]N-[2-(Diethylamino)ethyl3-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamidedihydrochloride

[2422] The title compound was obtained from N,N-diethylethylenediamineby the method similar to that in Example 155. Yield: 47%.

[2423] Amorphous.

[2424]¹H NMR (DMSO-d₆) δ1.22 (6H, t, J=7.4 Hz), 1.24 (6H, s), 1.48 (6H,s), 2.20 (2H, s), 3.12-3.32 (4H, m), 3.62-3.81 (6H, m), 3.95 (3H, s),7.12 (1H, s), 7.72-7.81 (2H, m), 8.25-8.34 (2H, m).

Example 173

[2425]N-(8-Methyl-8-azabicyclo[3.2.1]oct-3-yl)-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro(2,3-h]isoquinolin-1-yl)benzamidedihydrochloride

[2426] The title compound was obtained using3-amino-8-methyl-8-azabicyclo[3.2.1]octane by the method-similar to thatin Example 155. Yield: 49%.

[2427] Amorphous.

[2428]¹H NMR (DMSO-d₆) δ1.23 (6H, s), 1.43 (6H, s), 2.17-2.80 (14H, m),2.96-3.22 (2H, m), 3.85 (2H, br s), 3.95 (3H, s), 7.12 (1H, s),7.72-7.79 (2H, m), 8.14-8.19 (1H, m), 8.27 (1H, s).

Example 174

[2429]N-(1-Azabicyclo[2.2.2]oct-3-yl)-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamidedihydrochloride

[2430] The title compound was obtained using3-amino-1-azabicyclo[2.2.2]octane by the method similar to that inExample 155. Yield: 49%.

[2431] Amorphous.

[2432]¹H NMR (DMSO-d₆) δ1.23 (6H, s), 1.48 (6H, s), 1.88-2.38 (7H, m),3.18-3.83 (8H, m), 3.97 (3H, s), 4.27-4.48 (1H, m), 7.12 (1H, s),7.70-7.78 (2H, m), 8.22-8.33 (1H, m), 8.43 (1H, s).

Example 175

[2433]N-(2-Amino-2-oxoethyl)-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide

[2434] The title compound was obtainedfrom-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoic-acidhydrochloride and glycinamide hydrochloride by the method similar tothat in Example 159. Yield: 31%.

[2435] Melting point: 135-136° C. (ethyl acetate-hexane).

[2436]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.31 (6H, s), 2.18 (2H, s), 2.70(2H, s), 3.92 (3H, s), 4.13 (2H, d, J=5.0 Hz), 5.85 (1H, br s),6.56-6.65 (2H, m), 7.44-7.57 (3H, m), 7.86 (2H, d, J=8.0 Hz).

Example 176

[2437]2-Methyl-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoyl]alanineethyl ester

[2438] Triethylamine (0.938 mL, 6.72 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.479 g,2.50 mmol) were added to a solution of3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid hydrochloride (0.80 g, 1.92 mmol), 1-hydroxy-1H-benzotriazolemonohydrate (0.324 g. 2.11 mmol), ethyl 2-aminoisobutyrate hydrochloride(0.355 g, 2.11 mmol) in N,N-dimethylformamide (4 mL) and the mixture wasstirred at room temperature for 2 hours. The reaction mixture wascombined with water, and extracted with ethyl acetate. The extract waswashed with water, and then concentrated under reduced pressure. Theresidue was subjected to a column chromatography on a basic silica gel(ethyl acetate/methanol 1:1), and recrystallized from diisopropylether-hexane to obtain the title compound (0.63 g, Yield: 67).

[2439] Melting point: 114-115° C.

[2440]¹H NMR (CDCl₃) 1.26 (6H, s), 1.28 (3H, t, J=7.0 Hz), 1.30 (6H, s),1.67 (6H, s), 2.17 (2H, s), 2.70 (2H, s), 3.93 (3H, s), 4.23 (2H, q,J=7.0 Hz), 6.62 (1H, s), 6.88 (1H, br s), 7.42-7.51 (2H, m), 7.81-7.91(2H, m).

Example 177

[2441]2-Methyl-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoyl]alaninehydrochloride

[2442] 1 M aqueous solution of sodium hydroxide (8.0 mL) was added to asolution of2-methyl-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoyl]alanineethyl ester (2.60 g, 5.28 mmol) in ethanol (10 mL) and the mixture wasstirred at room temperature for 12 hours. 1 M hydrochloric acid (13.5mL) was added to the reaction mixture and the mixture was concentratedunder reduced pressure. The residue was combined with ethanol andfiltered, and the filtrate was concentrated under reduced pressure, andthis procedure was repeated 3 times. The residue was crystallized fromethyl acetate to obtain the title compound (2.38 g, Yield: 90%).

[2443] Melting point: 197-201° C.

[2444]¹H NMR (DMSO-d₆) δ1.24 (6H, br s), 1.49 (6H, s), 1.53 (6H, s),2.22-2.30 (2H, m), 3.10-3.22 (2H, m), 3.95 (3H, s), 7.12 (1H, 5 5),7.65-7.78 (2H, m), 8.16-8.22 (1H, m), 8.30 (1H, s), 8.90 (1H, m).

Example 178

[2445]N-(2-Amino-1,1-dimethyl-2-oxoethyl)-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide

[2446] 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(0.920 g, 4.80 mmol) was added to a solution of2-methyl-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoyl]alaninehydrochloride (1.85 g, 3.69 mmol), 1-hydroxy-1H-benzotriazolemonohydrate (0.622 g, 4.06 mmol) in N,N-dimethylformamide (20 mL) andthe mixture was stirred at room temperature for 15 minutes. Conc.aqueous ammonia (3.7 mL) was added thereto and the mixture was stirredat room temperature further for 15 minutes. The reaction solution wascombined with water, and extracted with ethyl acetate. The extract waswashed with water, and then concentrated under reduced pressure. Theresidue was subjected to a column chromatography on a basic silica gel(ethyl acetate/hexane 9:1 followed by ethyl acetate/methanol 19:1), andthen recrystallized from ethyl acetate-diisopropyl ether to obtain thetitle compound (1.05 g, Yield: 61%).

[2447] Melting point: 129-131° C.

[2448]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.31 (6H, s), 1.69 (6H, s), 2.19(2H, s), 2.70 (2H, s), 3.93 (3H, s), 5.58 (1H, br s), 6.48 (1H, br s),6.62 (1H, s), 7.11 (1H, s), 7.42-7.48 (2H, m), 7.86-7.90 (2H, m).

Example 179

[2449]N-Methyl-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide

[2450] 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(0.479 g, 2.50 mmol) was added to a solution of3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid hydrochloride (0.80 g, 1.92 mmol), 1-hydroxy-1H-benzotriazolemonohydrate (0.324 g, 2.11 mmol) in N,N-dimethylformamide (4 mL) and themixture was stirred at room temperature for 20 minutes. 40% solution ofmethylamine/methanol (1.0 mL) was added to the reaction mixture and themixture was stirred at room temperature further for 2 hours. Thereaction solution was combined with water, and extracted with ethylacetate. The extract was washed with water, and then concentrated underreduced pressure. The residue was recrystallized from ethylacetate-diisopropyl ether to obtain the title compound (0.39 g, Yield:62%).

[2451] Melting point: 206-207° C.

[2452]¹H NMR (CDCl₃) δ1.24 (6H, s), 1.29 (6H, s), 2.16 (2H, s), 2.67(2H, s), 2.98 (3H, d, J=4.6 Hz), 3.93 (3H, s), 6.58-6.70 (1H, 20 m),6.62 (1H, s), 7.40-7.48 (2H, m), 7.78 (1H, s), 7.83-7.90 (1H, m).

[2453] (Alternative synthetic method)

[2454] A mixture of1-(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-2-methyl-1-propanol(1.13 g, 4.50 mmol), 3-cyano-N-methylbenzamide (0.60 g, 3.75 mmol),acetic acid (4 mL) and toluene (6 mL) was cooled with ice, and conc.sulfuric acid (0.519 mL, 9.75 mmol) was added thereto. The mixture wasstirred at 80° C. for 1 hour, and then the reaction solution was allowedto cool to room temperature, and combined with water. This was washedwith diethyl ether, and then the aqueous layer was basified with conc.aqueous ammonia, and extracted with ethyl acetate. The extract waswashed with water, and concentrated under reduced pressure. The residuewas crystallized from ethyl acetate-hexane to obtain 0.79 g of thematerial. This was recrystallized from ethyl acetate to obtain the titlecompound (0.61 g, Yield: 42%).

[2455] Melting point: 202-203° C.

Example 180

[2456]N-Ethyl-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide

[2457] The title compound was obtained from3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid hydrochloride and a 70% aqueous solution of ethylamine by themethod similar to that in Example 157. Yield: 58%.

[2458] Melting point: 186-187° C. (ethyl acetate-diisopropyl ether).

[2459]¹H NMR (CDCl₃) δ1.24 (3H, t, J=5.4 Hz), 1.25 (6H, s), 1.30 (6H,s), 2.17 (2H, s), 2.69 (2H, s), 3.41-3.55 (2H, m), 3.93 (3H, s),6.38-6.45 (1H, m), 6.62 (1H, s), 7.42-7.48 (2H, m), 7.78 (1H, s),7.85-7.91 (1H, m).

Example 181

[2460]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-N-phenyl-1-furo[2,3-h]isoquinolinamine

[2461] Phosphorus pentoxide (0.68 g, 2.41 mmol) was added to a solutionofN-[2-(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-1,1-dimethylethyl]-N′-phenylurea(0.68 g, 1.85 mmol) in phosphorus oxychloride (3 mL) and the mixture wasstirred at 80° C. for 10 minutes. The reaction mixture was added to anexcessive saturated aqueous solution of sodium hydrogen carbonate, andthe mixture was extracted with ethyl acetate. The extract was washedwith water, and then concentrated under reduced pressure. The residuewas subjected to a column chromatography on a silica gel (hexane/ethylacetate 3:2) to obtain the title compound (0.34 go Yield: 52%). Analiquot was recrystallized from hexane-ethyl acetate.

[2462] Melting point: 135-136° C.

[2463]¹H NMR (CDCl₃) δ1.17 (6H, s), 1.51 (6H, s), 2.79 (2H, s), 3.53(2H, s), 3.91 (3H, s), 4.59 (1H, br s), 6.52 (1H, s), 6.88-6.93 (2H, m),6.95-7.04 (1H, m), 7.29-7.37 (2H, m).

Example 182

[2464]3,4,8,9-Tetrahydro-6-methoxy-N-(4-methoxyphenyl)-3,3,8,8-tetramethyl-1-furo[2,3-h]isoquinolinamine

[2465] A mixture ofN-[2-(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-1,1-dimethylethyl]-N′-(4-methoxyphenyl)urea(1.00 g, 2.51 mmol), phosphorus oxychloride (1.92 g, 12.6 mmol) andtoluene (10 mL) was stirred at room temperature for 2 hours, and at 80°C. further for 30 minutes. The reaction mixture was poured intoexcessive aqueous solution of sodium hydroxide, and extracted with ethylacetate. The extract was washed with water, and then concentrated underreduced pressure. The residue was subjected to a column chromatographyon a silica gel (hexane/ethyl acetate 2:3) to obtain the title compound(0.50 g, Yield: 52%). An aliquot was recrystallized from hexane-ethylacetate.

[2466] Melting point: 139-140° C.

[2467]¹H NMR (CDCl₃) δ1.17 (6H, s), 1.51 (6H, s), 2.78 (2H, s), 3.53(2H, s), 3.80 (3H, s), 3.90 (3H, s), 4.62 (1H, br s), 6.52 (1H, s),6.81-6.93 (4H, m).

Example 183

[2468]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-(1-piperidinyl)furo[2,3-h]isoquinolinehydrochloride

[2469] A free base of the title compound was obtained fromN-[2-(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-1,1-dimethylethyl]-1-piperidinecarboxamideby the method similar to that in Example 182. This was dissolved inethanol. 4 M solution of hydrogen chloride/ethyl acetate was added tothe reaction mixture and the mixture was concentrated under reducedpressure. The residue was recrystallized from ethanol-diethyl ether toobtain the title compound. Yield: 20%.

[2470] Melting point: 137-139° C.

[2471]¹H NMR (DMSO-d₆) δ1.22 (6H, s), 1.42 (6H, s), 1.64-(6H, s), 2.86(2H, s), 3.12 (2H, s), 3.42-3.75 (4H, m), 3.86 (3H, s), 6.96 (1H, s),9.31 (1H, s).

Example 184

[2472]8′,9′-Dihydro-6′-methoxy-8′,8′-dimethyl-1′-phenylspiro[cyclohexane-1,3(4′H)-furo[2,3-h]isoquinoline]hydrochloride

[2473] Conc. sulfuric acid (0.333 mL, 6.24 mmol) was added to a solutionof5-(cyclohexylidenemethyl)-2,3-dihydro-7-methoxy-2,2-dimethylbenzofuran(0.85 g, 3.12 mmol) and benzonitrile (0.350 mL, 3.43 mmol) in aceticacid (4 mL) and the mixture was stirred at 80° C. for 10 minutes. Thereaction solution was added to an aqueous solution of sodium hydroxide,and the mixture was extracted with.ethyl acetate. The extract was washedwith water, and then concentrated under reduced pressure. The residuewas subjected to a column chromatography on a silica gel (hexane/ethylacetate 3:1) to obtain a free base (0.54 g, Yield: 46%) of the titlecompound as an oil. This was dissolved in ethanol. 4 M solution ofhydrogen chloride/ethyl acetate was added to the mixture and the mixturewas concentrated under reduced pressure. The residue was precipitatedfrom ethanol-diisopropyl ether to obtain the title compound (0.51 g,Yield: 40%).

[2474] Amorphous.

[2475]¹H NMR (DMSO-d₆) δ1.22 (6H, s), 1.25-1.85 (10H, m), 2.15 (2H, s),3.31 (2H, s), 3.94 (3H, s), 7.19 (1H, s), 7.58-7.80 (5H, m).

Example 185

[2476]8′,9′-Dihydro-6′-methoxy-1′-(4-methoxyphenyl)-8′,8′-dimethylspiro[cyclohexane-1,3′(4′H)-furo[2,3-h]isoquinoline]hydrochloride

[2477] The title compound was obtained using 4-methoxybenzonitrile bythe method similar to that in Example 184. Yield: 45%.

[2478] Amorphous.

[2479]¹H NMR (DMSO-d₆) δ1.25 (6H, s), 1.32-1.80 (10H, m), 2.31 (2H, s),3.33 (2H, s), 3.88 (3H, s), 3.92 (3H, s), 7.14 (1H, s), 7.16 (2H, d,J=8.6 Hz), 7.55 (2H, d, J=8.6 Hz).

Example 186

[2480]3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-6-(1-methylethoxy)-1-phenylfuro[2,3-h]isoquinolinehydrochloride

[2481] A free base of the title compound was obtained from3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenyl-6-furo[2,3-h]isoquinolinoland 2-iodopropane by the method similar to that in Example 99. This wasdissolved in hexane and 4 M solution of hydrogen chloride/ethyl acetatewas added thereto. The mixture was concentrated under reduced pressure,and crystallized from hexane-ethyl acetate to obtain the title compound.Yield: 71%.

[2482] Melting point: 154-155° C.

[2483]¹H NMR (DMSO-d₆) δ1.22 (6H, s), 1.33 (6H, d, J=6.0 Hz), 1.44 (6H,s), 2.15 (2H, s), 3.15 (2H, s), 4.82-4.95 (1H, m), 7.10 (1H, s),7.62-7.77 (5H, m).

Example 187

[2484]6-(Cyclopentyloxy)-3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinoline

[2485] The title compound was obtained from3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenyl-6-furo[2,3-h]isoquinolinoland bromocyclopentane by the method similar to that in Example 99.Yield: 43%.

[2486] Melting point: 73-74° C. (hexane).

[2487]¹H NMR (CDCl₃) δ1.24 (6H, s), 1.28 (6H, s), 1.55-2.00 (8H, m),2.15 (2H, s), 2.66 (2H, s), 4.84-4.92 (1H, m), 6.59 (1H, s), 7.38 (5H,s).

Example 188

[2488]3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin-6-ylacetate hydrochloride

[2489] Acetic anhydride (2 mL) was added to a solution of3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenyl-6-furo[2,3-h]isoquinolinol(567 mg, 1.76 mmol) in pyridine (2 mL) and the mixture was stirred atroom temperature for 12 hours. A saturated aqueous solution of sodiumhydrogen carbonate was poured into the reaction mixture, which was thenextracted twice with ethyl acetate. The combined organic layer waswashed with water and brine, dried over magnesium sulfate, filtered, andconcentrated under reduced pressure. The residue was subjected to acolumn chromatography on a silica gel (hexane/ethyl acetate 3:1) toobtain a free base of the title compound. This was dissolved in ethylacetate, combined with 4 M solution of hydrogen chloride/ethyl acetate,concentrated under reduced pressure, and crystallized from hexane-ethylacetate to obtain the title compound (533 mg, Yield: 76%).

[2490] Melting point: 155-165° C.

[2491]¹H NMR (DMSO-d₆) δ1.23 ( 1.45 (6H, s), 2.37 (2H, s), 2.31 (3H, s),3.16 (2H, s), 7.22 (1H, s), 7.66-7.80 (5H, m).

Example 189

[2492]3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin-6-ylbenzoate hydrochloride

[2493] The title compound was obtained from benzoyl chloride by themethod similar to that in Example 188. Yield: 75%.

[2494] Melting point: 160-165° C. (ethyl acetate).

[2495]¹H NMR (DMSO-d₆) δ1.23 (6H, s), 1.47 (6H, s), 2.28 (2H, s), 3.18(2H, s), 7.34 (1H, s), 7.60-7.85 (8H, m), 8.14 (2H, d, J=7.4 Hz).

Example 190

[2496]6-Butoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinoline

[2497] Sodium hydride (66% suspension in oil) (61 mg, 1.69 mmol) and1-iodobutane (0.19 mL, 1.65 mmol) were added sequentially to a solutionof3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenyl-6-furo[2,3-h]isoquinolinol(495 mg, 1.54 mmol) in N,N-dimethylformamide (5 mL) and the mixture wasstirred at room temperature for 2 hours. The reaction mixture was pouredinto water, and extracted twice with ethyl acetate. The combined organiclayer was washed with water (twice) and a brine, dried over magnesiumsulfate, filtered, and concentrated under reduced pressure. The residuewas subjected to a column chromatography on a silica gel (hexane/ethylacetate 5:1 followed by 3:1), and recrystallized from hexane to obtainthe title compound (357 mg, Yield: 61%).

[2498] Melting point: 99-101° C.

[2499]¹H NMR (CDCl₃) δ0.98 (3H, t, J=7.4 Hz), 1.25-(6H, s), 1.29 (6H,s), 1.39-1.58 (2H, m), 1.68-1.90 (2H, m), 2.17 (2H, s), 2.67 (2H, s),4.10 (2H, t, J=7.0 Hz), 6.60 (1H, s), 7.38 (5H, 5).

Example 191

[2500]3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-1-phenyl-6-propoxyfuro[2,3-h]isoquinolinehydrochloride

[2501] A free base of the title compound was obtained using1-iodopropane by the method similar to that in Example 190. This wasdissolved in ethyl acetate, combined with 4 M solution of hydrogenchloride/ethyl acetate, and concentrated under reduced pressure toobtain the title compound. Yield: 91%.

[2502] Amorphous.

[2503]¹H NMR (DMSO-d₆) δ0.97 (3H, t, J=7.3 Hz), 1.23 (6H, s), 1.44 (6H,s), 1.68-1.88 (2H, m), 2.16 (2H, s), 3.15 (2H, s), 4.14 (2H, t, J=6.8Hz), 7.10 (1H, s), 7.60-7.80 (5H, m).

Example 192

[2504]3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-1-phenyl-6-(phenylmethoxy)furo[2,3-h]isoquinoline

[2505] The title compound was obtained using benzyl bromide by themethod similar to that in Example 190. Yield: 74%.

[2506] Melting point: 129-131° C. (diethyl ether-hexane).

[2507]¹H NMR (CDCl₃), δ1.22 (6H, s), 1.31 (6H, s), 1.18 (2H, s), 2.62(2H, s), 5.23 (2H, s), 6.60 (1H, s), 7.30-7.48 (10H, m).

Example 193

[2508]3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-1-phenyl-6-(2-pyridinylmethoxy)furo[2,3-h]isoquinolinedihydrochloride

[2509] A free base of the title compound was obtained using2-(chloromethyl)pyridine hydrochloride by the method similar to. that inExample 190. This was dissolved in ethyl acetate, combined with 4 Msolution of hydrogen chloride/ethyl acetate, concentrated under reducedpressure, and crystallized from ethanol-ethyl acetate to obtain thetitle compound. Yield: 90%.

[2510] Melting point: 170-210° C.

[2511]¹H NMR (CDCl₃) δ1.33 (6H, s), 1.69 (6H, s), 2.25 (2H, s), 3.05(2H, s), 5.92 (2H, s), 7.09 (1H, s), 7.57-7.74 (5H, m), 7.85-7.95 (1H,m), 8.20 (1H, d, J=76Hz), 8.42-8.56 (1H, m), 8.75 (1H, d, J=4.8 Hz).

Example 194

[2512]3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-1-phenyl-6-(3-pyridinylmethoxy)furo[2,3-h]isoquinoline

[2513] The title compound was obtained from 3-(chloromethyl)pyridinehydrochloride by the method similar to that in Example 190. Yield: 85%.

[2514] Melting point: 112-115° C. (hexane).

[2515]¹H NMR (CDCl₃) δ1.31 (6H, s), 1.32 (6H, s), 2.19 (2H, s), 2.70(2H, s), 5.26 (2H, s), 6.64 (1H, s), 7.33 (1H, d, J=7.4, 4.8 Hz), 7.43(5H, s), 7.80 (1H, dd, J=7.4, 1.6 Hz), 8.59 (1H, dd, J=4.8, 1.6 Hz),8.68 (1H, d, J=1.6 Hz).

Example 195

[2516]3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-1-phenyl-6-(4-pyridinylmethoxy)furo[2,3-h]isoquinoline

[2517] The title compound was obtained from 4-(chloromethyl)pyridinehydrochloride by the method similar to that in Example 190. Yield: 79%.

[2518] Melting point: 122-124° C. (hexane).

[2519]¹H NMR (CDCl₃) δ1.22 (6H, s), 1.32 (6H, s), 2.19 (2H, s), 2.61(2H, s), 5.25 (2H, s), 6.53 (1H, s), 7.36 (2H, d, J=6.2 Hz), 7.38 (5H,s), 8.61 (2H, d, J=6.2 Hz).

Example 196

[2520]3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-1-phenyl-6-[(3-phenyl-2-propenyl)oxy]furo[2,3-h]isoquinoline

[2521] The title compound was obtained using cinnamyl chloride by themethod similar to that in Example 190. Yield: 78%.

[2522] Melting point: 121-123° C. (hexane-diethyl ether).

[2523]¹H NMR (DMSO-d₆) δ1.13 (6H, s), 1.21 (6H, s), 2.18 (2H, s), 2.63(2H, s), 4.78 (2H, d, J=6.0 Hz), 6.45-6.59 (1H, m), 6.78 (1H, d, J=16.8Hz), 6.88 (1H, s), 7.28-7.52 (10H, m).

Example 197

[2524]3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-1-phenyl-6-(3-phenylpropoxy)furo[2,3-h]isoquinolinehydrochloride

[2525] A free base of the title compound was obtained using1-bromo-3-phenylpropane by the method similar to that in Example 190.This was dissolved in ethyl acetate, combined with 4 M solution ofhydrogen chloride/ethyl acetate, concentrated under reduced pressure,and crystallized from hexane to obtain the title compound. Yield: 89%.

[2526] Melting point: 165-180° C.

[2527]¹H NMR (DMSO-d₆) δ1.24 (6H, s), 1.45 (6H, s), 2.02-2.16 (2H, m),2.17 (2H, s), 2.74 (2H, t, J=8.0 Hz), 3.14 (2H, s), 4.19 (2H, t, J=6.0Hz), 7.07 (1H, s), 7.18-7.38 (5H, m), 7.63-7.80 (5H, m), 12.68 (1H, brs).

Example 198

[2528]3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-1-phenyl-6-[(5-phenylpentyl)oxy]furo[2,3-h]isoquinoline

[2529] The title compound was obtained using 1-bromo-5-phenylpentane bythe method similar to that in Example 190. Yield: 79%.

[2530] Melting point: 104-106° C. (hexane).

[2531]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.29 (6H, s), 1.45-1.94 (6H, m),2.17 (2H, s), 2.64 (2H, t, J=7.8 Hz), 2.67.(2H, s), 4.09 (2H, t, J=6.8Hz), 6.58 (1H, s), 7.17-7.35 (5H, m), 7.38 (5H, s).

Example 199

[2532] Ethyl(3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin-6-yl)carbonate hydrochloride

[2533] A free base of the title compound was obtained using ethylchloroformate by the method similar to that in Example 190. This wasdissolved in ethyl acetate, combined with 4 M solution of hydrogenchloride/ethyl acetate, concentrated under reduced pressure, andcrystallized from hexane-ethyl acetate to obtain the title compound.Yield: 71%.

[2534] Melting point: 144-147° C.

[2535]¹H NMR (DMSO-d₆) δ1.24 (6H, s), 1.29 (3H, t, J=8 7.1 Hz), 1.45(6H, s), 2.25 (2H, s), 3.16 (2H, s), 4.28 (2H, q, J=7.1 Hz), 7.33 (1H,s), 7.65-7.80 (5H, m).

Example 200

[2536]3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-1-phenyl-6-[(1-phenyl-1H-tetrazol-5-yl)oxy]furo[2,3-h]isoquinoline

[2537] The title compound was obtained using 5-chloro-1-phenyl1H-tetrazole by the method similar to that in Example 190. Yield: 88%.

[2538] Melting point: 191-193° C. (diethyl ether).

[2539]¹H NMR (CDCl₃) δ1.24 (6H, s), 1.27 (6H, s), 2.24 (2H, s), 2.71(2H, s), 7.09 (1H, s), 7.41 (5H, s), 7.50-7.62 (3H, m), 7.82-7.88 (2H,m).

Example 201

[2540]6-(Fluoromethoxy)-3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinoline

[2541] The title compound was obtained using bromofluoromethane by themethod similar. to that in Example 190. Yield: 75%.

[2542] Melting point: 120-122° C. (hexane-diethyl ether).

[2543]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.31 (6H, s), 2.21 (2H, s), 2.69(2H, s), 5.80 (2H, d, J=54.2 Hz), 6.85 (1H, s), 7.40 (5H, s).

Example 202

[2544]2-[[(3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin-6-yl)oxy]methyl]-1H-isoindole-1,3(2H)-dione

[2545] The title compound was obtained using N-(bromomethyl)phthalimideby the method similar to that in Example 190. Yield: 92%.

[2546] Melting point: 191-193° C. (diethyl ether).

[2547]¹H NMR (CDCl₃) δ1.20 (6H, s), 1.24 (6H, s), 2.16 (2H, s), 2.62(2H, s), 5.73 (2H, s), 6.77 (1H, s), 7.38 (5H, s), 7.75-7.79 (2H, m),7.89-7.94 (2H, m).

Example 203

[2548][(3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin-6-yl)oxy]aceticacid methyl ester

[2549] The title compound was obtained using methyl bromoacetate by themethod similar to that in Example 190. Yield: 72%.

[2550] Melting point: 82-84° C. (hexane-diethyl ether).

[2551]¹H NMR (CDCl₃) δ1.24 (6H, s), 1.29 (6H, s), 2.17 (2H, s), 2.65(2H, s), 3.81 (3H, s), 4.78 (2H, s), 6.57 (1H, s), 7.38 (5H, s).

Example 204

[2552]2-[(3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin-6-yl)oxy]acetamide

[2553] 5 M solution of ammonia/methanol (7 mL) was added to a mixture of[(3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin-6-yl)oxy]aceticacid methyl ester (501 mg, 1.27 mmol) and sodium cyanide (6.2 mg, 0.127mmol) and the mixture was stirred in sealed tube at 45° C. for 5 hours.ethanol was distilled off under reduced pressure, and water was pouredinto the residue, which was then extracted twice with ethyl acetate. Thecombined organic layer was washed with brine, dried over magnesiumsulfate, filtered, and concentrated under reduced pressure. Theresultant crystals were washed with diethyl ether to obtain the titlecompound (409 mg, Yield: 85%).

[2554] Melting point: 117-119° C.

[2555]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.30 (6H, s), 2.20 (2H, s), 2.68(2H, s), 4.62 (2H, s), 5.63 (1H, br s), 6.63 (1H, s), 6.80 (1H, br s),7.39 (5H, s).

Example 205

[2556][(3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin-6-yl)oxy]acetatehydrochloride.

[2557] 2 M aqueous solution of sodium hydroxide (3.13 mL, 6.26 mmol) wasadded to a solution of[(3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin-6-yl)oxy]aceticacid methyl ester (1.23 g, 3.13 mmol) in methanol (6 mL) and the mixturewas stirred at room temperature for 4 hours. Methanol was distilled offunder reduced pressure, and water was poured into the residue, which wasthen neutralized with 2 M hydrochloric acid. 4 M solution of hydrogenchloride/ethyl acetate (1.17 mL, 4.68 mmol) was added to the mixture andthe mixture was concentrated under reduced pressure. The residue wasdissolved in methanol, and the insolubles were filtered off, and motherliquor was concentrated under reduced pressure. The same procedure wasrepeated twice, and then the title compound (1.17 g, Yield: 90%) wasobtained.

[2558] Amorphous.

[2559]¹H NMR (CDCl₃) δ1.29 (6H, s), 1.54 (6H, s), 2.18 (2H, s), 2.93(2H, s), 4.66 (2H, s), 6.66 (1H, s), 7.48-7.70 (5H, m).

Example 206

[2560]N-Methyl-2-[(3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin-6-yl)oxy]acetamidehydrochloride.

[2561] N,N′-Carbonyldiimidazole (187 mg, 1.15 mmol) was added to asolution of[(3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin-6-yl)oxy]acetatehydrochloride (435 mg, 1.05 mmol) in N,N-dimethylformamide (4 mL) andthe mixture was stirred at room temperature for 2 hours. Methylaminehydrochloride (78 mg, 1.15 mmol) and triethylamine (0.32 mL, 2.31 mmol)were added, and the mixture was stirred at room temperature further for5 hours. Ice water was poured into the reaction mixture, which was thenextracted twice with ethyl acetate. The combined organic layer waswashed twice with brine, dried over magnesium sulfate, filtered, andconcentrated under reduced pressure. The residue was subjected to acolumn chromatography on a silica gel (hexane/ethyl acetate 1:1 followedby ethyl acetate) to obtain a free base of the title compound. This wasdissolved in ethyl acetate, combined with 4 M solution of hydrogenchloride/ethyl acetate, and concentrated under reduced pressure toobtain the title compound (330 mg, Yield: 73%).

[2562] Amorphous.

[2563]¹H NMR (DMSO-d₆) δ1.24H, s), 1.44 (6H, s), 2.17 (2H, s), at 2.66(3H, d, J=4.8 Hz), 3.13 (2H, s), 4.72 (2H, s), 6.99 (1H, 20 s),7.63-7.80 (5H, m), 8.17 (1H, d, J=4.8 Hz).

Example 207

[2564]N,N-Dimethyl-2-[(3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin-6-yl)oxylacetamide

[2565] Triethylamine (0.22 mL, 1.60 mmol) was added to a solution of[(3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin-6-yl)oxy]aceticacid hydrochloride (604 mg, 1.45 mmol) in tetrahydrofuran (6 mL) and themixture was stirred at room temperature for 3 minutes.N,N′-carbonyldiimidazole (259 mg, 1.60 mmol) was added to the reactionmixture and the mixture was stirred at room temperature for 2 hours. 2 Msolution of dimethylamine/tetrahydrofuran (0.80 mL, 1.60 mmol) was addedto the reaction mixture and the mixture was stirred at room temperaturefor 1 hour. Water was poured into the mixture, which was then extractedtwice with ethyl acetate. The combined organic layer was washed withbrine, dried over sodium sulfate, filtered, and concentrated underreduced pressure. The residue was crystallized from ethylacetate-diethyl ether to obtain the title compound (422 mg, Yield: 72%).

[2566] Melting point: 120-140° C.

[2567]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.29 (6H, s), 2.17 (2H, s), 2.69(2H, s), 2.99 (3H, s), 3.10 (3H, s), 4.83 (2H, s), 6.67 (1H, s), 7.39(5H, s).

Example 208

[2568]2-[(3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin-6-yl)oxylethanamine

[2569] Sodium hydride (66% suspension in oil) (142 mg, 3.92 mmol) wasadded to a solution of3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenyl-6-furo[2,3-h]isoquinolinol(1.20 g, 3.73 mmol) in N,N-dimethylformamide (6 mL) and the mixture wasstirred at room temperature for 15 minutes. N-(2-Bromoethyl)phthalimide(949 mg, 3.73 mmol) was added to the reaction mixture, and the mixturewas stirred at room temperature for 1 hour, and then at 60° C. for 3hours. N-(2-bromoethyl)phthalimide (949 mg, 3.73 mmol) and potassiumcarbonate (542 mg, 3.92 mmol) were added at room temperature, and themixture was stirred at 50° C. for 3 hours. Water was poured into thereaction mixture, which was then extracted twice with ethyl acetate. Thecombined organic layer was washed twice with water and brine, dried oversodium sulfate, filtered, and concentrated under reduced pressure. Theresidue was subjected to a column chromatography on a silica gel(hexane/ethyl acetate 50:1 followed by ethyl acetate) to obtain2-[2-[(3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin-6-yl)oxy]ethyl]-1H-isoindole-1,3(2H)-dione(707 mg, Yield: 38%).

[2570]¹H NMR (CDCl₃) δ1.21 (6H, s), 1.22 (6H, s), 2.13 (2H, s), 2.62(2H, s), 4.12 (2H, t, J=6.4 Hz), 4.39 (2H, t, J=6.4 Hz), 6.70 (1H, s),7.35-7.37 (5H, m), 7.70-7.75 (2H, m), 7.84-7.88 (2H, m).

[2571]2-[2-[(3,4,8,-9-tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin-6-yl)oxy]ethyl]-1H-isoindole-1,3(2H)-dione(708 mg, 1.42 mmol) was dissolved in ethanol (7 mL), hydrazinemonohydrate (0.072 mL, 1.50 mmol) was added thereto, and the mixture wasstirred at 80° C. for 1.5 hours. The insolubles were removed byfiltration, and the filtrate was concentrated under reduced pressure. Adilute aqueous solution of sodium hydroxide was poured into the residue,which was then extracted twice with ethyl acetate. The combined organiclayer was washed with brine, dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was subjected to acolumn chromatography on a silica gel (hexane/ethyl acetate 3:1 followedby ethyl acetate), and crystallized from hexane-diethyl ether to obtainthe title compound (56 mg, Yield: 11%).

[2572] Melting point: 77-79° C.

[2573]¹H NMR (CDCl₃) δ1.24 (6H, s), 1.30 (6H, s), 2.18 (2H, s), 2.67(2H, s), 3.11 (2H, t, J=5.3 Hz), 4.08-4.18 (2H, m), 6.63 (1H, s), 7.38(5H, s).

Example 209

[2574]2-[(3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin-6-yl)oxy]ethanol

[2575] 2-Bromoethanol (0.11 mL, 1.57 mmol) and potassium carbonate (217mg, 1.57 mmol) were added to a solution of3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenyl-6-furo[2,3-h]isoquinolinol(459 mg, 1.43 mmol) in N,N-dimethylformamide (4.5 mL), and the mixturewas stirred at 60° C. for 36 hours. Water was poured into the reactionmixture, which was then extracted twice with ethyl acetate. The combinedorganic layer was washed with water and brine (twice), dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas subjected to a column chromatography on a basic silica gel(hexane/ethyl acetate 3:1 followed by 1:1), and crystallized fromhexane-diethyl ether to obtain the title compound (366 mg, Yield: 70%).

[2576] Melting point: 90-92° C.

[2577]¹H NMR (CDCl₃) δ1.25 H, s), 1.30 (6H, s), 2.19 (2H, s), 2.67 (2H,s), 3.92-3.98 (2H, m), 4.21 (2H, d, J=4.4 Hz), 6.65 (1H, s), 7.39 (5H,s).

Example 210

[2578]6-(2-Fluoroethoxy)-3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinoline

[2579] The title compound was obtained using 1-bromo-2-fluoroethane bythe method similar to that in Example 209. Yield: 56%.

[2580] Melting point: 77-79° C. (diethyl ether-hexane).

[2581]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.30 (6H, s), 2.18 (2H, s), 2.67(2H, s), 4.29-4.47 (2H, m), 4.64-4.92 (2H, m), 6.65 (1H, s), 7.39 (5H,s).

Example 211

[2582] Dimethylcarbamothioic acidO-(3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin-6-yl)ester

[2583] The title compound was obtained using dimethylthiocarbamoylchloride by the method, similar to that in Example 209. Quantitative.

[2584] Amorphous.

[2585]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.27 (6H, s), 2.19 (2H, s), 2.69(2H, s), 3.34 (3H, s), 3.45 (3H, s), 6.76 (1H, s), 7.35-7.47 (5H, m).

Example 212

[2586] Dimethylcarbamothioic acidO-(3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin-6-yl)esterhydrochloride

[2587] Dimethylcarbamothioic acidO-(3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin-6-yl)ester(902 mg, 2.21 mmol) was dissolved in ethyl acetate and combined with 4 Mhydrogen chloride/ethyl acetate solution (0.55 mL). The resultantmixture was concentrated under reduced pressure to obtain crystals,which were washed with diethyl ether to obtain the title compound (946mg, yield: 96%).

[2588] Melting point: 170-180° C.

[2589]¹H NMR (DMSO-d₆) δ1.22 (6H, s), 1.46 (6H, s), 2.22 (2H, s), 3.18(2H, s), 3.30 (3H, s), 3.36 (3H, s), 7.17 (1H, s), 7.66-7.82 (5H, m).

Example 213

[2590] Dimethylcarbamothioic acidS-(3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin-6-yl)esterhydrochloride

[2591] Dimethylcarbamothioic acidO-(3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin-6-yl)ester(4.92 g, 12.0 mmol) was stirred at 190° C. for 24 hours. The reactionmixture was subjected to a column chromatography on a silica gel(hexane/ethyl acetate 5:1 followed by 3:1) to obtain a free base of thetitle compound.

[2592]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.29 (6H, s), 2.21 (2H, s), 2.68(2H, s), 3.05 (3H, br s), 3.10 (3H, br s), 7.11 (1H, s), 7.40 (5H, s).

[2593] This was dissolved in ethyl acetate, combined with 4 M hydrogenchloride/ethyl acetate solution, concentrated under reduced pressure,crystallized from hexane-diethyl ether to obtain the title compound.(404mg, yield: 8.2%).

[2594] Melting point: 146-148° C.

[2595]¹H NMR (DMSO-d₆) δ1.23 (6H, s), 1.45 (6H, s), 2.25 (2H, s), 2.94(3H, s), 3.06 (3H, s), 3.15 (2H, s), 7.40 (1H, s), 7.66-7.77 (5H, s).

Example 214

[2596]3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-6-(methylthio)-1-phenylfuro[2,3-h]isoquinolinehydrochloride

[2597] A solution of dimethylcarbamothioic acidS-(3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin-6-yl)ester (539 mg, 1.32 mmol) in 10% aqueoussolution of potassium hydroxide (5 mL) was heated under reflux for 1hour. Water was poured into the reaction mixture, which was neutralizedwith 2 M hydrochloric acid and extracted twice with ethyl acetate. Thecombined organic layer was washed with brine, dried over sodium sulfate,filtered and concentrated under reduced pressure to obtain3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenyl-6-furo[2,3-h]isoquinolinethiol(434 mg).

[2598] This was dissolved in N,N-dimethylformamide (5 mL), sodiumhydride (66% dispersion in oil) (57 mg, 1.58 mmol) was added thereto,and the mixture was stirred at room temperature for 20 minutes. Whilecooling in ice, iodomethane (0.098 mL, 1.58 mmol) was added thereto, andthe mixture was stirred at room temperature for 1 hour. Water was pouredinto the reaction mixture, which was extracted twice with ethyl acetate.The combined organic layer was washed with.brine, dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas subjected to a column chromatography on a basic silica gel(hexane/ethyl acetate 10:1 followed by 5:1) to obtain a free base of thetitle compound. This was dissolved in ethyl acetate, combined with 4 Mhydrogen chloride/ethyl acetate solution, concentrated under reducedpressure to obtain the title compound (287 mg, yield: 56%).

[2599] Amorphous.

[2600]¹H NMR (DMSO-d₆) δ1.24 (6H, s), 1.45 (6H, s), 2.20 (2H, s), 2.57(3H, s), 3.17 (2H, s), 7.20 (1H, s), 7.64-7.80 (5H, m).

Example 215

[2601]6-Chloro-3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro(2,3-h]isoquinolinehydrochloride

[2602] Phosphorus oxychloride (0.44 mL, 4.67 mmol) was added to asolution of3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenyl-6-furo[2,3-h]isoquinolinol(1.00 g, 3.11 mmol) in N,N-dimethylformamide (1 mL) and the mixture wasstirred at 90° C. for 15 hours and then at 130° C. for 3 hours. Thereaction mixture was poured into 2 M aqueous solution of sodiumhydroxide and extracted twice with ethyl acetate. The combined organiclayer was washed with water and brine, dried over sodium sulfate,filtered and concentrated under reduced pressure. The residue wassubjected to a column chromatography on a basic silica gel (hexane/ethylacetate 100:1 followed by 30:1) to obtain a free base of the titlecompound. This was dissolved in ethyl acetate, combined with 4 Mhydrogen chloride/ethyl acetate solution, concentrated under reducedpressure, crystallized from hexane-ethyl acetate to obtain the titlecompound (380 mg, yield: 33%).

[2603] Melting point: 165-167° C.

[2604]¹H NMR (CDCl₃) δ1.36 (6H, s), 1.71 (6H, s), 2.31 (2H, s), 3.01(2H, s), 7.21 (1H, s), 7.55-7.75 (5H, m).

Example 216

[2605]6-Chloro-3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-[3-(4-pyridinyl)phenyl]furo[2,3-h]isoquinolinedihydrochloride

[2606] The title compound was obtained from3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-[3-(4-pyridinyl)phenyl]-6-furo[2,3-h]isoquinolinolby the method similar to that in EXAMPLE 215. Yield: 30%.

[2607] Melting point: 145-155C (ethanol-ethyl acetate).

[2608]¹H NMR (DMSO-d₆) δ1.27 (6H, s), 1.50 (6H, s), 2.40 (2H, s), 3.17(2H, s), 7.51 (1H, s), 7.85-7.87 (2H, m), 8.37-8.39 (2H, m), 8.47 (2H,d, J=6.3 Hz), 9.13 (2H, d, J=6.3 Hz).

Example 217

[2609]3,4,8,9-Tetrahydro-N,3,3,8,8-pentamethyl-1-phenyl-6-furo2,3-h]isoquinolinaminehydrochloride

[2610] 40% Methylamine/methanol solution (5 mL) was added to a mixtureof3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinoline(518 mg, 1.54 mmol) and ammonium chloride (165 mg, 3.09 mmol) and themixture was stirred in a sealed tube at 150° C. for 15 hours. Methanolwas distilled off under reduced pressure, and water was poured into theresidue, and the mixture was extracted twice with ethyl acetate. Thecombined organic layer was washed with water and brine, dried overmagnesium sulfate, filtered and concentrated under reduced pressure. Theresidue was subjected to a column chromatography on a silica gel(hexane/ethyl acetate 3:1 followed by hexane/ethyl acetate/triethylamine25:25:1) to obtain a free base of the title compound.

[2611]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.30 (6H, s), 2.16 (2H, s), 2.72(2H, s), 2.93 (3H, s), 6.31 (1H, s), 7.40 (5H, s).

[2612] This was dissolved in ethyl acetate, combined with 4 M hydrogenchloride/ethyl acetate solution and concentrated under reduced pressureto obtain the title compound (376 mg, yield: 76%).

[2613] Amorphous.

[2614]¹H NMR (CDCl₃) δ1.28 (6H, s), 1.67 (6H, s), 2.19 (2H, s), 2.96(2H, s), 3.03 (3H, s), 6.35 (1H, s), 7.50-7.70 (5H, m).

Example 218

[2615]3,4,8,9-Tetrahydro-N,N,3,3,8,8-hexamethyl-1-phenyl-6-furo[2,3-h]isoquinolinaminedihydrochloride

[2616] A mixture of3,4,8,9-tetrahydro-N,3,3,8,8-pentamethyl-1-phenyl-6-furo[2,3-h]isoquinolinamine(321 mg, 0.865 mmol), 37% aqueous solution of formaldehyde (0.14 mL,1.90 mmol) and formic acid (0.16 mL, 4.33 mmol) was stirred at 60° C.for 1.5 hours and at 100° C. for 1 hour. The reaction mixture wasneutralized with 2 M aqueous solution of sodium hydroxide and extractedtwice with ethyl acetate. The combined organic layer was washed withbrine, dried over sodium sulfate, filtered, and concentrated underreduced pressure. The residue was subjected to a column chromatographyon a basic silica gel (hexane/ethyl acetate 100:1 followed by 10:1) toobtain a free base of the title compound. This was dissolved in ethylacetate, combined with 4 M hydrogen chloride/ethyl acetate solution andcrystallized from ethyl acetate to obtain the title compound (114 mg,yield: 31%).

[2617] Melting point: 105-115° C.

[2618]¹H NMR (DMSO-d₆) δ1.22 (6H, s), 1.41 (6H, s), 2.05 (2H, s), 3.05(2H, s), 3.16 (6H, s), 6.64 (1H, s), 7.53-7.73 (5H, m), 11.69 (1H, brs).

Example 219

[2619]N-Ethyl-3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenyl-6-furo[2,3-h]isoquinolinaminehydrochloride

[2620] The title compound was obtained from 70% aqueous solution ofethylamine by the method similar to that in EXAMPLE 217. Yield: 21%.

[2621] Amorphous.

[2622]¹H NMR (DMSO-d₆) δ1.24 (6H, s), 1.40 (6H, s), 1.70 (3H, t, J=7.4Hz), 2.09 (2H, s), 3.04 (2H, s), 3.26-3.50 (2H, m), 6.59 (1H, s), 7.08(1H, br s), 7.52-7.84 (5H, m), 11.37 (1H, br s).

Example 220

[2623]3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-1-phenyl-6-furo[2,3-h]isoquinolinamine

[2624] 5 M Ammonia/methanol solution (40 mL) was added to a mixture of3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinoline(3.77 g, 11.2 mmol) and ammonium chloride (1.20 g, 22.5 mmol) and themixture was stirred in a sealed tube at 150° C. for 24 hours. Methanolwas distilled off under reduced pressure, and water was poured into theresidue, which was neutralized with sodium hydrogen carbonate, andextracted three times with ethyl acetate. The combined organic layer waswashed with brine dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The residue was subjected to a columnchromatography on a basic silica gel (hexane/ethyl acetate 50:1 followedby 5:1) and crystallized from diethyl ether to obtain the title compound(1.58 g, yield: 44%).

[2625] Melting point: 158-162° C.

[2626]¹H NMR (CDCl₃) δ1.26 (12H, s), 2.15 (2H, s), 2.63 (2H, s), 6.40(1H, s), 7.36-7.44 (5H, m).

Example 221

[2627]N-(3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin-6-yl)formamide

[2628] A solution of formic acid (3 mL) and acetic anhydride (1 mL) wasstirred at room temperature for 1.5 hours, and3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenyl-6-furo[2,3-h]isoquinolinamine(500 mg, 1.56 mmol) was added thereto and the mixture was stirred atroom temperature for 2 hours. The reaction mixture was poured into 3.5 Maqueous solution of sodium hydroxide and extracted twice with ethylacetate. The combined organic layer was washed with brine, dried oversodium sulfate, filtered and concentrated under reduced pressure toobtain the title compound (470 mg, yield: 87%).

[2629] Amorphous.

[2630]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.29 (6H, s), 2.22 (2H, s), 2.69(0.6H, s), 2.73 (1.4H, s), 7.40 (6H, s), 8.03 (1H, s), 8.45 (1H, d,J=1.4 Hz).

Example 222

[2631]N-(3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2.3-]isoquinolin-6-yl)acetamide

[2632] Acetic anhydride (2 mL) was added to a solution of3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenyl-6-furo[2,3-h]isoquinolinamine(542 mg, 1.69 mmol) in pyridine (3 mL) and the mixture was stirred atroom temperature for 12 hours. Aqueous solution of.sodium hydrogencarbonate was poured into the reaction mixture, and the mixture wasextracted three times with ethyl acetate. The combined organic layer waswashed with brine, dried over magnesium sulfate, filtered andconcentrated under reduced pressure. The residue was subjected to acolumn chromatography on a basic silica gel (hexane/ethyl acetate 5:1)and crystallized from hexane-diethyl ether to obtain the title compound(445 mg, yield: 74%).

[2633] Melting point: 175-180° C.

[2634]¹H NMR (CDCl₃) δ1.24 (6H, s), 1.28 (6H, s), 2.20 (2H, s), 2.22(3H, s), 2.71 (2H, s), 7.32 (1H, s), 7.83 (5H, s), 8.04 (1H, br s).

Example 223

[2635]N-(3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin-6-yl)methanesulfonamide

[2636] While cooling in ice, methanesulfonyl chloride (0.22 mL, 2.74mmol) was added to a solution of3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenyl-6-furo[2,3-h]isoquinolinamine(400 mg, 1.25 mmol) and triethylamine (0.38 mL, 2.74 mmol) intetrahydrofuran (5 mL ) and the mixture was stirred at room temperaturefor 2 hours. Water was poured into the reaction mixture, which wasneutralized with 1 M aqueous solution of sodium hydroxide and extractedtwice with ethyl acetate. The combined organic layer was washed withwater and brine, dried over sodium sulfate, filtered and concentratedunder reduced pressure. The residue was subjected to a columnchromatography on a silica gel (hexane/ethyl acetate 5:1 followed by1:1) and crystallized from diethyl ether to obtain the title compound(27 mg, yield: 5.4%).

[2637] Melting point: 175-177° C.

[2638]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.28 (6H, s), 2.21 (2H, s), 2.70(2H, s), 3.06 (3H, s), 7.17 (1H, s), 7.39 (5H, s).

Example 224

[2639]N-(3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin-6-yl)propanamide

[2640] The title compound was obtained from3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenyl-6-furo[2,3-h]isoquinolinamineand propionyl chloride by the method similar to that in EXAMPLE 30.Yield: 57%.

[2641] Melting point: 129-131° C. (diethyl ether-hexane).

[2642]¹H NMR (CDCl₃) δ1.24 (6H, s), 1.26 (3H, t, J=7.5 Hz), 1.28 (6H,s), 2.20 (2H, s), 2.44 (2H, q, J=7.5 Hz), 2.70 (2H, s), 7.31 (1H, s),7.38-(5H, s), 8.07 (1H, br s).

Example 225

[2643](3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin-6-yl)carbamicacid ethyl ester.

[2644] The title compound was obtained from3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenyl-6-furo[2,3-h]isoquinolinamineand ethyl chloroformate by the method similar to that in EXAMPLE 30.Yield: 3.2%.

[2645] Melting point: 92-94° C. (diethyl ether-hexane).

[2646]¹H NMR (CDCl₃) δ1.24 (6H, s), 1.27 (6H, s), 1.33 (3H, t, J=7.1Hz), 2.19 (2H, s), 2.70 (2H, s), 4.25 (2H, q, J=7.1 Hz), 6.81 (1H, s),7.38 (5H, s), 7.70 (1H, br s).

Example 226

[2647]N-(3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin-6-yl)glycineethyl ester

[2648] The title compound was obtained from3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenyl-6-furo[2,3-h]isoquinolinamineand ethyl bromoacetate by the method similar to that in EXAMPLE 209.Yield: 35%.

[2649] Melting point: 79-81° C. (diethyl ether-hexane).

[2650]¹H NMR (CDCl₃) δ1.23 (6H, s), 1.26 (6H, s), 1.31 (3H, t, J=7.1Hz), 2.15 (2H, s), 2.64 (2H, s), 3.98 (2H, d, J=5.8 Hz), 4.27 (2H, q,J=7.1 Hz), 4.52 (1H, t, J=5.8 Hz), 6.20 (1H, s), 7.37 (5H, s).

Example 227

[2651]N-(3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin-6-yl)urea

[2652] While cooling with ice, trifluoroacetic acid (0.34 mL, 4.43 mmol)was added to a suspension of3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenyl-6-furo[2,3-h]isoquinolinamine(346 mg, 1.08 mmol) and sodium cyanate (140 mg, 2.16 mmol) in toluene (5mL) and the mixture was stirred at room temperature for 3 hours. 1 Maqueous solution of sodium hydroxide was poured into the mixture, andthe mixture was extracted twice with ethyl acetate. The combined organiclayer was washed with brine, dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was subjected to acolumn chromatography on a basic silica gel (hexane/ethyl acetate 3:1followed by 1:2), and the resultant crystals were washed with diethylether to obtain the title compound (178 mg, yield: 45%).

[2653] Melting point: 151-153° C.

[2654]¹H NMR (CDCl₃) δ1.24 (6H, s), 1.26 (6H, s), 2.19 (2H, s), 2.70(2H, s), 4.85 (2H, br s), 6.72 (1H, s), 7.37 (5H, s), 7.72 (1H, s).

Example 228

[2655]N-Methyl-N′-(3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin-6-yl)urea

[2656] While cooling with ice, phenyl chloroformate (0.22 mL, 1.67 mmol)was added to a solution of3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenyl-6-furo[2,3-h]isoquinolinamine(485 mg, 1.51 mmol) and triethylamine (0.23 mL, 1.67 mmol) inN,N-dimethylformamide (6 mL) and the mixture was stirred at roomtemperature for 4 hours. Triethylamine (0.12 mL, 0.84 mmol) and phenylchloroformate (0.11 mL, 0.84 mmol) were further added, and the mixturewas stirred at room temperature further for 4 hours. Methylaminehydrochloride (305 mg, 4.53 mmol) and triethylamine (0.63 mL, 4.53 mmol)were added to the reaction mixture and the mixture was stirred at roomtemperature for 15 hours. Ice water was poured into the mixture and themixture was extracted twice with ethyl acetate. The combined organiclayer was washed with water (twice) and brine, dried over magnesiumsulfate, filtered and concentrated under reduced pressure. The residuewas subjected to a column chromatography on a basic silica gel(hexane/ethyl acetate 3:1 followed by 1:1) and crystallized from diethylether to obtain the title compound (305 mg, yield: 54%).

[2657] Melting point: 209-211° C.

[2658]¹H NMR (CDCl₃) δ1.24 (6H, s), 1.25 (6H, s), 2.18 (2H, s), 2.69(2H, s), 2.86 (3H, d, J=5.0 Hz), 4.86 (1H, br q, J=5.0 Hz), 6.41 (1H,s), 7.37 (5H, s), 7.75 (1H, s).

Example 229

[2659]2-[(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin-5-yl)methyl]-1H-isoindol-1,3(2H)-dione

[2660]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinoline(796 mg, 2.37 mmol) was dissolved in conc. sulfuric acid (3 mL),N-(hydroxymethyl)phthalimide (462 mg, 2.61 mmol) was added thereto andthe mixture was stirred at room temperature for 2 hours. Water waspoured into the reaction mixture, which was extracted twice with ethylacetate. The combined organic layer was washed with water and brine,dried over sodium sulfate, filtered and concentrated under reducedpressure. The residue was subjected to a column chromatography on abasic silica gel (hexane/ethyl acetate 8:1 followed by 5:1) and theresultant crystals were washed with diethyl ether to obtain the titlecompound (506 mg, yield: 43%).

[2661] Melting point: 193-195° C.

[2662]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.28 (6H, s), 2.12 (2H, s), 2.81(2H, s), 3.96 (3H, s), 4.92 (2H, s), 7.37 (5H, s), 7.69-7.71 (2H, m),7.81-7.85 (2H, m).

Example 230

[2663]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenyl-5-furo[2,3-h]isoquinolinemethanamine

[2664] Hydrazine monohydrate (0.71 mL, 14.7 mmol) was added to asuspension of2-[(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin-5-yl)methyl]-1H-isoindol-1,3(2H)-dione(6.94 g, 14.0 mmol) in ethanol (40 mL) and the mixture was heated underreflux for 3 hours. Diisopropyl ether was poured into the reactionmixture and the precipitated crystals were removed off by filtration.The filtrate was combined with 1 M aqueous solution of sodium hydroxideand water, and the organic layer was separated and the aqueous layer wasextracted with ethyl acetate. The organic layer was washed with brine,dried over sodium sulfate, filtered and concentrated under reducedpressure. The residue was subjected to a column chromatography on asilica gel (ethyl acetate followed by ethyl acetate/triethylamine 50:1)and crystallized from hexane-diethyl ether to obtain the title compound(3.46 g, yield: 68%).

[2665] Melting point: 140-142 CC.

[2666]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.28 (6H, s), 2.13 (2H, s), 2.71(2H, s), 3.86 (2H, s), 3.97 (3H, s), 7.38 (5H, s).

Example 231

[2667]N-[(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin-5-yl)methyl]formamide

[2668] The title compound was obtained from3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenyl-5-furo[2,3-h]isoquinolinemethanamineby the method similar to that in EXAMPLE 221. Yield: 84%.

[2669] Melting point: 205-208° C. (diethyl ether-hexane).

[2670]¹H NMR (CDCl₃) δ1.23 (6H, s), 1.28(6H, s), 2.14 (2H, s), 2.79 (2H,s), 4.00 (3H, s), 4.53 (2H, d, J=5.4 Hz), 5.86 (1H, br 9). 7.37 (5H, s),8.17 (1H, s).

Example 232

[2671]N-[(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin-5-yl)methyl]acetamide

[2672] The title compound was obtained from3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenyl-5-furo[2,3-h]isoquinolinemethanamineby the method similar to that in EXAMPLE 30. Yield: 90%.

[2673] Melting point: 164-166° C. (diethyl ether-hexane).

[2674]¹H NMR (CDCl₃) δ1.23 (6H, s), 1.28 (6H, s), 1.97 (3H, s), 2.14(2H, s), 2.78 (2H, s), 3.99 (3H, s), 4.48 (2H, d, J=5.6 Hz), 5.74 (1H,br s), 7.38 (5H, s).

Example 233

[2675]N-[(3,4,8,9-Tetrahydro-6-methoxy-3,3,-8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin-5-yl)methyl]urea

[2676] The title compound was obtained from3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenyl-5-furo[2,3-h]isoquinolinemethanamineby the method similar to that in EXAMPLE 227. Yield: 59%.

[2677] Melting point: 172-174° C. (diethyl ether-hexane).

[2678]¹H NMR (CDCl₃) δ1.24 (6H, s), 1.27 (1.8H, s), 1.28 (4.2H, s), 1.58(2H, s), 2.13 (0.6H, s), 2.14 (1.4H, s), 2.77 (2H, s), 3.98 (2.1H, s),4.00 (0.9H, s), 4.38 (1.4H, d, J=5.8 Hz), 4.45-4.58 (1.4H, m), 4.46(0.6H, d, J=5.8 Hz), 4.80-4.95 (0.6H, m), 7.33-7.38 (5H, m).

Example 234

[2679]5-Bromomethyl-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinoline

[2680] Conc. sulfuric acid (3.39 mL, 63.6 mmol) was added to asuspension of3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinoline(7.12 g, 21.2 mmol), paraformaldehyde (94%) (1.02 g, 31.8 mmol) andsodium bromide (2.51 g, 24.4 mmol) in acetic acid (6.07 mL, 106 mmol)and the mixture was stirred at 90° C. for 5 hours. Ice water was pouredinto the reaction mixture, which was washed with diethyl ether,neutralized with con. aqueous ammonia, and extracted twice with ethylacetate. The combined organic layer was washed with water and brine,dried over sodium sulfate, filtered and concentrated under reducedpressure. The residue was subjected to a column chromatography on asilica gel (hexane/ethyl acetate 7:1 followed by 5:1) to obtain thetitle compound (4.57 g, yield: 50%).

[2681] Amorphous.

[2682]¹H NMR (CDC1₃) δ1.28 (12H, s), 2.14 (2H, s), 2.71 (2H, s), 4.03(3H, s), 4.65 (2H, s), 7.38 (5H, s).

Example 235

[2683]3,4,8,9-Tetrahydro-6-methoxy-5-(methoxymethyl)-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolinehydrochloride

[2684] 28% sodium methoxide/methanol-solution (0.91 mL, 4.73 mmol) wasadded to a solution of5-bromomethyl-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinoline(1.84 g, 4.30 mmol) in methanol (10 mL) and the mixture was stirred atroom temperature for 1 hour and then at 60° C. for 1 hour. Furthermore28% sodium methoxide/methanol solution (1.82 mL, 9.46 mmol) was added tothe mixture and the mixture was stirred at 60° C. for 1 hour. Thereaction mixture was concentrated under reduced pressure, and theresidue was combined with water and extracted twice with ethyl acetate.The combined organic layer was washed with water and brine, dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresidue was subjected to a column chromatography on a basic silica gel(hexane/ethyl acetate 7:1) to obtain a free base of the title compound.This was dissolved in ethyl acetate, combined with 4 M hydrogenchloride/ethyl acetate solution (0.77 mL), and the resultant crystalswere washed with ethyl acetate to obtain the title compound (1.16 g,yield: 65%).

[2685] Melting point: 143-145° C.

[2686]¹H NMR (DMSO-d₆) δ1.26 (6H, s), 1.44 (6H, s), 2.16 (2H, s), 3.15(2H, s), 3.29 (3H, s), 3.99 (3H, s), 4.50 (2H, s), 7.63-7.66 (5H, m).

Example 236

[2687]5-(Ethoxymethyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolinehydrochloride

[2688] Sodium acetate (143 mg, 1.75 mmol) and 2 M aqueous solution ofsodium hydroxide (2 mL) were added to a solution of5-bromomethyl-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinoline(374 mg, 0.873 mol) in ethanol (3 mL) and the mixture was stirred at 60°C. for 2 hours and then at 80° C. for 2 hours. Ice water was poured intothe reaction mixture, which was extracted twice with ethyl acetate. Thecombined organic layer was washed with brine, dried over sodium sulfate,filtered, and concentrated under reduced pressure. The residue wassubjected to a column chromatography on a silica gel (hexane/ethylacetate 5:1) to obtain a free base of the title compound. This wasdissolved in ethyl acetate, combined with 4 M hydrogen chloride/ethylacetate solution, concentrated under reduced pressure and crystallizedfrom diethyl ether to obtain the title compound (191 mg, yield: 51%).

[2689] Melting point: 137-139° C.

[2690]¹H NMR (DMSO-d₆) δ1.14 (3H, t, J=7.2 Hz), 1.26 (6H, s), 1.44(6H,s), 2.16 (2H, s), 3.16 (2H, s), 3.49 (2H, q, J=7.2 Hz), 3.99 (3H, s),4.54 (2H, s), 7.63-7.78 (5H, m).

Example 237

[2691]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenyl-5-furo[2,3-h]isoquinolinemethanol

[2692] A suspension of5-bromomethyl-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinoline(289 mg, 0.675 mmol) and calcium carbonate (506 mg, 5.06 mmol) in1,4-dioxane (3 mL) and water (3 mL). was stirred at 60° C. for 2 hours.Water was poured into the reaction mixture, which was extracted twicewith ethyl acetate. The combined organic layer was washed with brine,dried over sodium sulfate, filtered, and concentrated under reducedpressure. The residue was subjected to a column chromatography on abasic silica gel (hexane/ethyl acetate 3:1) and crystallized fromhexane-diethyl ether to obtain the title compound.(159 mg, yield: 65%).

[2693] Melting point: 160-163° C.

[2694]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.28 (6H, s), 1.97 (1H, t, J=6.0Hz), 2.14 (2H, s), 2.75 (2H, s), 4.00 (3H, s), 4.74 (2H, d, J=6.0 Hz),7.38 (5H, s).

Example 238

[2695]5-(Fluoromethyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolinehydrochloride

[2696] Potassium fluoride (spray dried material) (118 mg, 2.02 mmol) and18-crown-6 (534 mg, 2.02 mmol) were added to a solution of5-bromomethyl-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinoline(289 mg, 0.675 mmol) in acetonitrile (5 mL) and the mixture was stirredat 80° C. for 7 hours. Acetonitrile was distilled off under reducedpressure, and water was poured into the residue and the mixture wasextracted twice with ethyl acetate. The combined organic layer waswashed with brine, dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The residue was subjected to a columnchromatography on a basic silica gel (hexane/ethyl acetate 10:1 followedby 5:1) to obtain a free base of the title compound. This was dissolvedin ethyl acetate, combined with 4 M hydrogen chloride/ethyl acetatesolution, crystallized from diethyl ether to obtain the title compound(230 mg, yield: 84%).

[2697] Melting point: 146-158° C.

[2698]¹H NMR (DMSO-d₆) δ1.26 (6H, s), 1.45 (6H, s), 2.15-2.23 (2H, m),3.22 (2H, s), 4.04 (3H, s), 5.57 (2H, d, J=48.0 Hz), 7.63-7.80 (5H, m).

Example 239

[2699]3,4,8,9-Tetrahydro-6-methoxy-3,3,5,8,8-pentamethyl-1-phenylfuro[2,3-h]isoquinolinehydrochloride

[2700] Tributyltin hydride (0.91 mL, 4.73 mmol) and2,2′-azobis(isobutyronitrile) (11 mg, 0.0677 mmol) were added to asolution of5-bromomethyl-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinoline(290 mg, 0.677 mmol) in chlorobenzene (3 mL) and the mixture was stirredat 80° C. for 2 hours. Chlorobenzene was distilled off under reducedpressure and the residue was subjected to a column chromatography on abasic silica gel (hexane/ethyl acetate 10:1) to obtain a free base ofthe title compound. This was dissolved in ethyl acetate, combined with 4M hydrogen chloride/ethyl acetate solution, and crystallized from ethylacetate to obtain the title compound (63 mg, yield: 24%).

[2701] Melting point: 138-140° C.

[2702]¹H NMR (DMSO-d₆) δ1.24 (6H, s), 1.45 (6H, s), 2.12 (2H, s), 2.17(3H, s), 3.08 (2H, s), 3.99 (3H, s), 7.58-7.76 (5H, m).

Example 240

[2703]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenyl-5-furo[2,3-h]isoquinolineacetonitrile

[2704] A solution of potassium cyanide (143 mg, 2.20 mmol) in water(2.25 mL) was added to a solution of5-bromomethyl-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinoline(947 mg, 2.20 mmol) in N,N-dimethylformamide (9.5 mL) and the mixturewas stirred at room temperature for 3 hours. Water was poured into thereaction mixture, which was extracted twice with ethyl acetate. Thecombined organic layer was washed twice each with water and brine, driedover sodium sulfate, filtered and concentrated under reduced pressure.The residue was subjected to a column chromatography on a silica gel(hexane/ethyl acetate 5:1 followed by 3:1) and crystallized fromhexane-diethyl ether to obtain the title compound (465 mg, yield: 56%).

[2705] Melting point: 95-96° C.

[2706]¹H NMR (CDCl₃) δ1.28 (6H, s), 1.28 (6H, s), 2.15 (2H, s), 2.68(2H, s), 3.74 (2H, s), 4.03 (3H, s), 7.38 (5H, s).

Example 241

[2707]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenyl-5-furo[2,3-h]isoquinolineaceticacid ethyl ester hydrochloride

[2708] While cooling in ice, conc. sulfuric acid (2.34 mL, 43.8 mmol)was added to a solution-of3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenyl-5-furo[2,3-h]isoquinolineacetonitrile(4.01 g, 10.7 mmol) in ethanol (36 mL) and the mixture was heated underreflux for 60 hours. Ice water was poured into the reaction mixture,which was neutralized with conc. aqueous ammonia, and then extractedtwice with ethyl acetate. The combined organic layer was washed withbrine, dried over sodium sulfate, filtered, and concentrated underreduced pressure. The residue was subjected to a column chromatographyon a basic silica gel (hexane/ethyl acetate 20:1 followed by 5:1) toobtain a free base of the title compound.

[2709]¹H NMR (CDCl₃) δ1.23 (6H, s), 1.28 (6H, s), 1.28 (3H, t, J=7.1Hz), 2.14 (2H, s), 2.59 (2H, s), 3.73 (2H, s), 3.92 (3H, s), 4.18 (2H,g, J=7.1 Hz), 7.38 (5H, s).

[2710] This was dissolved in ethyl acetate, combined with 4 M hydrogenchloride/ethyl acetate solution and concentrated under reduced pressureto obtain the title compound (2.58 g, yield: 53%).

[2711] Amorphous.

[2712]¹H NMR (DMSO-d₆) δ1.21 (3H, t, J=7.0 Hz), 1.26 (6H, s), 1.42 (6H,s), 2.17 (2H, s), 3.08 (2H, s), 3.78 (2H, s), 3.96 (3H, s), 4.91 (2H, q,J=7.0 Hz), 7.63-7.80 (5H, m).

Example 242

[2713]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenyl-5-furo[2,3-h]isoquinolineaceticacid

[2714] 5 M aqueous solution of sodium hydroxide (2 mL) was added to asolution of3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenyl-5-furo[2,3-h]isoquinolineaceticacid ethyl ester (750 mg, 1.78 mmol) in ethanol (5 mL) and the mixturewas stirred at room temperature for 5 hours. Ethanol was distilled offunder reduced pressure, and water was poured into the residue, and themixture was washed with diisopropyl ether. The aqueous layer wasadjusted at pH 3.5 with 2 M hydrochloric acid, combined with sodiumchloride, and extracted three times with tetrahydrofuran. The combinedorganic layer was dried over sodium sulfate, filtered, concentratedunder reduced pressure and crystallized from hexane-diethyl ether toobtain the title compound (176 mg, yield: 25%).

[2715] Melting point: 225-245° C.

[2716]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.27 (6H, s), 2.13 (2H, s), 2.61(2H, s), 3.74 (2H, s), 3.94 (3H, s), 7.38 (5H, s).

Example 243

[2717]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenyl-5-furo[2,3-h]isoquinolineacetamide

[2718] N,N′-Carbonyldiimidazole (226 mg, 1.40 mmol) was added to asolution of3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenyl-5-furo[2,3-h]isoquinolineaceticacid (499 mg, 1.27 mmol) in N,N-dimethylformamide (5 mL) and the mixturewas stirred at room temperature for 10 minutes. Powdered ammoniumchloride (75 mg, 1.40 mmol) and triethylamine (0.20 mL, 1.40 mmol) wereadded and stirred at room temperature for 1 hour and then at 60° C. for4 hours. Ice water was poured into the reaction mixture, which wasextracted twice with ethyl acetate. The combined organic layer waswashed with water and brine (twice), dried over sodium sulfate, filteredand concentrated under reduced pressure. The resultant crystals werewashed with diethyl ether to obtain the title compound (358 mg, yield:72%).

[2719] Melting point: 171-176° C.

[2720]¹H NMR (CDCl₃) δ1.27 (6H, s), 1.29 (6H, s), 2.15 (2H, s), 2.74(2H, s), 3.65 (2H, s), 4.00 (3H, s), 5.22 (1H, br s), 5.80 (1H, br s),7.40 (5H, s).

Example 244

[2721]3,4,8,9-Tetrahydro-6-methoxy-N,3,3,8,8-pentamethyl-1-phenyl-5-furo[2,3-h]isoquinolineaceetamide

[2722] The title compound was obtained from methylamine hydrochloride bythe method similar to that in EXAMPLE 243. Yield: 73%.

[2723] Melting point: 187-190° C. (hexane).

[2724]¹N NMR (CDCl₃) δ1.23 (6H, s), 1.30 (6H, s), 2.15 (2H, s), 2.69(2H, s), 2.76 (3H, d, J=5.2 Hz), 3.63 (2H, s), 3.96 (3H, s), 5.68 (1H,br s), 7.38 (5H, s).

Example 245

[2725]2-[(3,4,8,9-Tetrahydro-6-hydroxy-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolin-5-yl)methyl]-1H-isoindol-1,3(2H)-dione

[2726] The title compound was obtained from3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenyl-6-furo[2,3-h]isoquinolinolby the method similar to that in EXAMPLE 229. Yield: 16%.

[2727] Melting point.: 239-242° C. (diethyl ether-hexane).

[2728]¹H NMR (CDCl₃) δ1.28 (12H, s), 2.15 (2H, s), 2.98 (2H, s), 4.94(2H, s), 7.35 (5H, s), 7.73-7.77 (2H, m), 7.86-7.91 (2H, m), 8.08 (1H,br s).

Example 246

[2729]3,4,8,9-Tetrahydro-6-hydroxy-3,3,8,8-tetramethyl-1-phenyl-5-furo[2,3-h]isoquinolinemethanol

[2730] While cooling in ice,3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenyl-6-furo[2,3-h]isoquinolinol(200 mg, 0.622 mmol) was added to a solution of chloromethylmethyl ether(0.052 mL, 0.684 mmol) and aluminum chloride (91 mg, 0.684 mmol) in1,2-dichloroethane (2 mL) and the mixture was stirred at roomtemperature for 5 hours. The reaction mixture was poured into ice water,washed with diethyl ether, neutralized with 5 M aqueous solution ofsodium hydroxide and extracted twice with ethyl acetate. The combinedorganic layer was washed with water and brine, dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas subjected to a column chromatography on a silica gel (hexane/ethylacetate/triethylamine 25:25:1 followed by ethyl acetate/triethylamine50:1) and crystallized from hexane-ethyl acetate to obtain the titlecompound (31 mg, yield: 14%).

[2731] Melting point: 210-230° C.

[2732]¹H NMR (CDCl₃) δ1.28 (6H, s), 1.32 (6H, s), 2.13 (2H, s), 2.77(2H, s), 4.84 (2H, s), 7.34-7.44 (5H, m).

Example 247

[2733]1-(2-Bromophenyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolinehydrochloride

[2734] While cooling in ice, conc. sulfuric-acid (2.52 mL, 47.3 mmol)was added to a solution of 2-bromobenzonitrile (3.92 g, 21.5 mmol) intoluene (12 mL) and acetic acid (12 mL). And then, a solution of2,3-dihydro-7-methoxy-2,2-dimethyl-5-(2-methyl-1-propenyl)benzofuran(5.00 g, 21.5 mmol) in toluene (12 mL) was added thereto and the mixturewas stirred at 80° C. for 1 hour. Ice water was poured into the reactionmixture, and the aqueous layer was separated and neutralized with conc.aqueous ammonia and extracted twice with ethyl acetate. The combinedorganic layer was washed with water and brine, dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas subjected to a column chromatography on a basic silica gel(hexane/ethyl acetate 20:1 followed by 10:1) to obtain a free base ofthe title compound.

[2735]¹H NMR (CDCl₃) δ1.23 (3H, s), 1.29 (3H, s), 1.33 (3H, s), 1.38(3H, s), 2.00 (1H, d, J=16.1 Hz), 2.17 (1H, d, J=16.1 Hz), 2.68 (1H, d,J=15.7 Hz), 2.80 (1H, d, J=15.7 Hz), 3.91 (3H, s), 6.60 (1H, s),7.17-7.42 (3H, m), 7.56 (1H, d, J=8.0 Hz).

[2736] This was dissolved in ethyl acetate, combined with 4 M hydrogenchloride/ethyl acetate solution and concentrated under reduced pressureto obtain the title compound (3.27 g. yield: 34%).

[2737] Amorphous.

[2738]¹H NMR (DMSO-d₆) δ1.21 (3H, s), 1.24 (3H, s), 1.47 (3H, s), 1.50(3H, s), 1.99 (1H, d, J=16.4 Hz), 2.12 (1H, d, J=16.4 Hz), 3.11 (1H, d,J=17.2 Hz), 3.29 (1H, d, J=17.2 Hz), 3.95 (3H, s), 7.14 (1H, s),7.56-7.68 (3H, m), 7.89-7.93 (1H, m).

Example 248

[2739]1-[3-(2-Furanyl)phenyl]-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoqulnoline

[2740] Dichlorobis(triphenylphosphine)palladium(II) (53 mg, 0.0750 mmol)and copper (I) iodide (14 mg, 0.0750 mmol) were added to a suspension of1-(3-bromophenyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinoline(622 mg, 1.50 mmol) and tributyl-2-furanyltin (590 mg, 1.65 mmol) intetrahydrofuran (6 mL) and the mixture was heated under reflux for 24hours, and tributyl-2-furanyltin (590 mg, 1.65 mmol) was added theretoand the mixture was heated under reflux for 15 hours. The insolubleswere filtered off and the filtrate was concentrated under reducedpressure. The residue was subjected to a column chromatography on abasic silica gel (hexane/ethyl acetate 100:1 followed by 10:1) andcrystallized-from diethyl ether-hexane to obtain the title compound (114mg, yield: 19%).

[2741] Melting point: 126-128° C.

[2742]¹H NMR (CDCl₃) δ1.27 (6H, s), 1.30 (6H, s), 2.27 (2H, s), 2.71(2H, s), 3.93 (3H, s), 6.46-6.49 (1H, m), 6.63 (1H, s), 6.68 (1H, d,J=3.4 Hz), 7.31-7.47 (3H, m), 7.69-7.74(2H, m).

Example 249

[2743]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-[4-(2-pyridinyl)phenyl]furo[2,3-h]isoquinolin

[2744] The title compound was obtained from1-(4-bromophenyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolineand tributyl-2-pyridinyltin by the method similar to that in EXAMPLE248. Yield: 50%.

[2745] Melting point: 127-129° C. (hexane).

[2746]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.30 (6H, s), 2.32 (2H, s), 2.70(2H, s), 3.93 (3H, s), 6.62 (1H, s), 7.22-7.30 (1H, m), 7.52 (2H, d,J=8.4 Hz), 7.76-7.79 (2H, m), 8.04 (2H, d, J=8.4 Hz), 8.72 (1H, d, J=4.8Hz).

Example 250

[2747]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-[2-(2-pyridinyl)phenyl]furo[2,3-h]isoquinoline

[2748] The title compound was obtained from1-(2-bromophenyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolineand tributyl-2-pyridinyltin by the method similar to that in EXAMPLE248. Yield: 9.5%.

[2749] Melting point: 120-122° C. (hexane-diethyl ether).

[2750]¹H NMR (CDCl₃) δ1.13 (3H, s), 1.17 (3H, s), 1.25 (3H, s), 1.28(3H, s), 1.98 (1H, d, J=16.2 Hz), 2.42 (1H, d, J=16.2 Hz), 2.64 (2H, s),3.85 (3H, s), 6.45 (1H, s), 6.99-7.06 (1H, m), 7.35-7.50 (5H, m),7.65-7.70 (1H, m), 8.41-8.44 (1H, m).

Example 251

[2751]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-[3-(2-pyridinyl)phenyl]furo[2,3-h]isoquinoline

[2752] The title compound was obtained from tributyl-2-pyridinyltin bythe method similar to that in EXAMPLE 248. Yield: 60%.

[2753] Melting point: 137-139° C. (diethyl ether-hexane).

[2754]¹H NMR (CDCl₃) δ1.28 (12H, s), 2.28 (2H, s), 2.71 (2H, s), 3.93(3H, s), 6.63 (1H, s), 7.20-7.25 (1H, m), 7.42-7.55 (2H, m), 7.74-7.77(2H, m), 8.03-8.07-(2H, m), 8.69 (1H, d, J=5.0 Hz).

Example 252

[2755]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-[3-(2-thienyl)phenyl]furo[2,3-h]isoquinoline

[2756] The title compound was obtained from tributyl-2-thienyltin by themethod similar to that in EXAMPLE 248. Yield: 37%.

[2757] Melting point: 172-175° C. (diethyl ether-hexane).

[2758]¹H NMR (CDCl₃) δ1.28 (6H, s), 1.31 (6H, s), 2.28 (2H, s), 2.72(2H, s), 3.94 (3H, s), 6.63 (1H, s), 7.06-7.10 (1H, m), 7.29-7.44 (4H,m), 7.62-7.69 (2H, m).

Example 253

[2759]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-[3-(5-pyrimidinyl)phenyl]furo[2,3-h]isoquinoline

[2760] Sodium (431 mg, 18.8 mmol) was added to a solution of naphthalene(2.20 g, 17.1 mmol) in 1,2-dimethoxyethane (20 mL) and the mixture wasstirred at room temperature for 1.5 hours. While cooling in ice,chlorotrimethyltin (2.91 g, 14.6 mmol) was added to the mixture andafter 10 minutes, 5-bromopyrimidine (2.0 g, 12.6 mmol) was added theretoand the mixture was stirred at room temperature for 2 hours.1,2-Dimethoxyethane was distilled off under reduced pressure, and waterwas poured into the residue, and the mixture was extracted twice withdiethyl ether. The combined organic layer was washed twice with waterand then with brine, dried over sodium sulfate, filtered, concentratedunder reduced pressure to obtain a mixture oftrimethyl-5-pyrimidinyltin, naphthalene and 5-bromopyrimidine.

[2761] This mixture was used to obtain the title compound by the methodsimilar to that in EXAMPLE 248. Yield: 32%.

[2762] Melting point: 141-143° C. (diethyl ether-hexane).

[2763]¹H NMR (CDCl₃) δ1.28 (6H, s), 1.31 (6H, s), 2.25 (2H, s), 2.73(2H, s), 3.94 (3H, s), 6.64 (1H, s), 7.46-7.67 (4H, m), 8.99 (2H, s),9.22 (1H, s).

Example 254

[2764]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-[2-(4-pyridinyl)phenyl]furo[2,3-h]isoquinoline

[2765] A solution of sodium carbonate (236 mg, 2.23 mol) in water (2 mL)and tetrakis(triphenylphosphine)palladium(0) (66 mg, 0.0567 mmol) wereadded to a solution of1-(2-bromophenyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinoline(558 mg, 1.35 mmol) and 4-pyridinylboronic acid (248 mg, 2.02 mmol) in1,2-dimethoxyethane (6 mL) and ethanol (2 mL) and the mixture wasstirred at 80° C. for 24 hours under nitrogen atmosphere. Water waspoured into the reaction mixture, which was extracted twice with ethylacetate. The combined organic layer was washed with brine, dried oversodium sulfate, filtered, and concentrated under reduced pressure. Theresidue was subjected to a column chromatography on a basic silica gel(hexane/ethyl acetate 20:1 followed by 3:1) and crystallized fromdiethyl ether-hexane to obtain the title compound (200 mg, yield: 36).

[2766] Melting point: 187-189° C.

[2767]¹H NMR (CDCl₃) δ1.09 (3H, s), 1.25 (3H, s), 1.28 (6H, s), 1.94(1H, d, J=16.3 Hz), 2.13 (1H, d, J=16.3 Hz), 2.60 (2H, s), 3.84 (3H, s),6.44 (1H, s), 7.24 (2H, d, J=6.2 Hz), 7.36-7.52 (4H, m), 8.44 (2H, d,J=6.2 Hz).

Example 255

[2768]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-[4-(4-pyridinyl)phenyl]furo[2,3-h]isoquinolinedihydrochloride

[2769] By the method similar to that In EXAMPLE 254 and starting from1-(4-bromophenyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinoline,a free base of the title compound was obtained. This was dissolved inethyl acetate, combined with 4 M hydrogen chloride/ethyl acetatesolution, concentrated under reduced pressure and crystallized fromethanol-ethyl acetate to obtain the title compound. Yield: 51%.

[2770] Melting point: 115-117° C.

[2771]¹H NMR (DMSO-d₆) δ1.23 (6H, s), 1.48 (6H, s), 2.70 (2H, s), 3.19(2H, s), 3.96 (3H, s), 7.13 (1H, s), 7.86 (2H, d, J=8.4 Hz), 8.27 (2H,d, J=8.4 Hz), 8.35 (2H, d, J=6.6 Hz), 8.96 (2H, d, J=6.6 Hz).

Example 256

[2772]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-[3-(3-pyridinyl)phenyl]furo[2,3-h]isoquinoline

[2773] The title compound was obtained from1-(3-bromophenyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolineand 3-(diethylboryl)pyridine by the method similar to that in EXAMPLE254. Yield: 70%.

[2774] Melting point: 116-117° C. (hexane-diethyl ether).

[2775]¹H NMR (CDCl₃) δ1.27 (6H, s), 1.30 (6H, s), 2.25 (2H, s), 2.72(2H, s), 3.93 (3H, s), 6.63 (1H, s), 7.33-7.63 (5H, m), 7.85-7.93 (1H,m), 8.58-8.61 (1H, m), 8.87 (1H, d, J=2.6 Hz).

Example 257

[2776]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-[4-(3-pyridinyl)phenyl]furo[2,3-h]isoquinolinedihydrochloride

[2777] By the method similar to that in EXAMPLE 254 and starting from1-(4-bromophenyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolineand 3-(diethylboryl)pyridine, a free base of the title compound wasobtained. This was dissolved in ethyl acetate, combined with 4 Mhydrogen chloride/ethyl acetate solution, concentrated under reducedpressure to obtain the title compound. Yield: 84%.

[2778] Amorphous.

[2779]¹H NMR (DMSO-d₆) δ1.22 (6H, s), 1.48 (6H, s), 2.29 (2H, s), 3.19(2H, s), 3.95 (3H, s), 7.13 (1H, s), 7.82 (2H, d, J=8.4 Hz), 7.92-7.99(1H, m), 8.16 (2H, d, J=8.4 Hz), 8.74 (1H, d, J=7.8 Hz), 8.87 (1H, d,J=5.0 Hz), 9.31 (1H, s).

Example 258

[2780]1-[3-(Benzofuran-2-yl)phenyl]-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinoline

[2781] The title compound was obtained from1-(3-bromophenyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolineand 2-benzofuranylboronic acid by the method similar to that in EXAMPLE254. Yield: 74%.

[2782] Melting point: 160-161° C. (hexane-diethyl ether).

[2783]¹H NMR (CDCl₃) δ1.29 (12H, s), 2.29 (2H, s), 2.32 (2H, s), 3.94(3H, s), 6.65 (1H, s), 7.07 (1H, s), 7.23-7.33 (2H, m), 7.37-7.61 (4H,m), 7.88-7.93 (2H, m).

Example 259

[2784]3′-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-amine

[2785] The title compound was obtained from1-(3-bromophenyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolineand 4-(1,3,2-dioxaborynan-2-yl)aniline by the method similar to that inEXAMPLE 254. Yield: 49%.

[2786] Melting point: 224-225° C. (ethyl acetate).

[2787]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.29 (6H, s), 2.26 (2H, s), 2.70(2H, s), 3.72 (2H, br s), 3.93 (3H, s), 6.62 (1H, s), 6.74 (2H, d, J=8.8Hz), 7.30-7.57 (4H, m), 7.43 (2H, d, J=8.8 Hz).

Example 260

[2788]N-[3′-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-yl]acetamide

[2789] The title compound was obtained from3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-amineby the method similar to that in EXAMPLE 30. Yield: 82%.

[2790] Melting point: 224-225° C. (diethyl ether-hexane).

[2791]¹H NMR (CDCl₃) δ1.27 (6H, s), 1.29 (6H, s), 2.18 (3H, s), 2.25(2H, s), 2.71 (2H, s), 3.93 (3H, s), 6.62 (1H, s), 7.32-7.60 (9H, m).

Example 261

[2792]N-[3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-yl]methanesulfonamide

[2793] The title compound was obtained from3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-amineand methanesulfonyl chloride by the method similar to that in EXAMPLE222. Yield: 81%.

[2794] Melting point: 228-230° C. (diethyl ether-hexane).

[2795]¹H NMR (CDCl₃) δ1.30 (12H, s), 2.25 (2H, s), 2.73 (2H, s), 2.89(3H, s), 3.93 (3H, s), 6.63 (1H, s), 7.22-7.57 (8H, m).

Example 262

[2796]3′-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-3-aminedihydrochloride

[2797] By the method similar to that in EXAMPLE 254 and starting from1-(3-bromophenyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolineand 3-aminophenylboronic acid hydrate, a free base of the title compoundwas obtained.

[2798]¹H NMR (CDCl₃)δ1.26 (6H, s), 1.30 (6H, s), 2.25 (2H, s), 2.71 (2H,s), 3.72 (2H, br s), 3.93 (3H, s), 6.62 (1H, s), 6.62-6.70 (1H, m), 6.92(1H, t, J=1.8 Hz), 6.96-7.03 (1H, m), 7.20 (1H, t, J=7.8 Hz), 7.32-7.48(2H, m), 7.54-7.62 (2H, m).

[2799] This was dissolved in ethyl acetate, combined with 4 M hydrogenchloride/ethyl acetate solution and concentrated under reduced pressureto obtain the title compound. Yield: 86%.

[2800] Amorphous.

[2801]¹H NMR (DMSO-d₆) δ1.21 (3H, s), 1.25 (3H, s), 1.45 (3H, s), 1.50(3H, s), 2.17-2.35 (2H, m), 3.08-3.30 (2H, m), 3.95 (3H, s), 7.12 (1H,s), 7.25-7.80 (8H, m).

Example 263

[2802]N-[3′-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-3-yl]acetamide

[2803] The title compound was obtained from3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-3-amineby the method similar to that in EXAMPLE 30. Yield: 64%.

[2804] Melting point: 217-218° C. (ethanol).

[2805]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.30 (6H, s), 2.17 (3H, s), 2.25(2H, s), 2.70 (2H, s), 3.93 (3H, s), 6.62 (1H, s), 7.32-7.66 (9H, m).

[2806] (Alternative Synthetic Method)

[2807] The title compound was obtained from1-(3-bromophenyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolineand 3-acetamidobenzenboronic acid by the method similar to that inEXAMPLE 254. Yield: 87%.

Example 264

[2808]2-Methyl-N-[3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-3-yl]alanineethyl ester hydrochloride

[2809] By the method similar to that in EXAMPLE 209 and starting from3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-3-amineand ethyl 2-bromoisobutyrate, a free base of the title compound wasobtained. This was dissolved in ethyl acetate, combined with 4 Mhydrogen chloride/ethyl acetate solution, concentrated under reducedpressure to obtain the title compound. Yield: 62%.

[2810] Amorphous.

[2811]¹H NMR (DMSO-d₆) δ1.07 (3H, t, J=7.0 Hz), 1.21 (6H, s), 1.48 (12H,s), 2.15-2.32 (2H, m), 3.19 (2H, s), 3.96 (3H, s), 4.07 (2H, q, J=7.2Hz), 6.50-7.92 (9H, m), 12.68 (1H, br s).

Example 265

[2812]N-[3′-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-3-yl]ureahydrochloride

[2813] By the method similar to that in EXAMPLE 227 and starting from3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-3-amine,a free base of the title compound was obtained. This was dissolved inethyl acetate, combined with 4 M hydrogen chloride/ethyl acetatesolution, concentrated under reduced pressure to obtain the titlecompound. Yield: 76%.

[2814] Amorphous.

[2815]¹H NMR (DMSO-d₆) δ1.21 (6H, s), 1.47 (6H, s), 2.27 (2H, s), 3.19(2H, s), 3.95 (3H, s), 6.00 (2H, br s), 7.12 (1H, s), 7.31-7.98 (8H, m),8.92 (1H, s), 12.63 (1H, br s).

Example-266

[2816]2,2,2-Trifluoro-N-[3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-3-yl]acetamide

[2817] The title compound was obtained from3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-3-amineand trifluoroacetic anhydride by the method similar to that in EXAMPLE222. Yield. 58%.

[2818] Melting point: 222-224° C. (diethyl ether). 1H NMR (CDCl₃) δ1.26(6H, s), 1.29 (6H, s), 2.23 (2H, s), 2.68 (2H, s), 3.93 (3H, s), 6.62(1H, s), 7.34-7.69 (8H, m), 8.67 (1H, br s).

Example 267

[2819]N-[3′-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-3-yl]methanesulfonamide

[2820] The title compound was obtained from3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,88-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-3-amine andmethanesulfonyl chloride by the method similar to that in EXAMPLE 222.Yield: 54%.

[2821] Melting point: 141-143° C. (diethyl ether-ethyl acetate).

[2822]¹H NMR (CDCl₃) δ1.30 (12H, s), 2.24 (2H, s), 2.73 (2H, s), 2.98(3H, s), 3.94 (3H, s), 6.64 (1H, s), 7.36-7.66 (8H, m).

Example 268

[2823]N-Methyl-N-[3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-3-yl]methanesulfonamidehydrochloride

[2824] By the method similar to that in EXAMPLE 190 and starting fromN-[3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-3-yl]methanesulfonamideand iodomethane, a free base of the title compound was obtained. Thiswas dissolved in ethyl acetate, combined with 4 M hydrogenchloride/ethyl acetate solution, concentrated under reduced pressure toobtain the title compound. Yield: 85%.

[2825] Amorphous.

[2826]¹H NMR (DMSO-d₆) δ1.21 (3H, s), 1.25 (3H, s), 1.45 (3H, s), 1.51(3H, s), 2.18-2.37 (2H, m), 2.89 (3H, s), 3.07-3.29 (2H, m), 3.32 (3H,s), 3.95 (3H, s), 7.12 (1H, s), 7.48-7.62 (3H, m), 7.74-7.83 (3H, m),8.00 (1H, s), 8.08 (1H, d, J=7.8 Hz).

Example 269

[2827]α,α-Dimethyl-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzeneacetonitrile

[2828] While cooling in ice, sodium hydride (66% dispersion in oil)(4.33 g, 119 mmol) was added to a solution of 4-cyanobenzeneacetonitrile(7.70 g, 54.2 mmol) in N,N-dimethylformamide (68 mL) and the mixture wasstirred at room temperature for 15 minutes. While cooling in ice,iodomethane (7.43 mL, 119 mmol) was added to the mixture and the mixturewas stirred at room temperature for 2 hours. The reaction mixture waspoured into ice water, and extracted twice with ethyl acetate. Thecombined organic layer was washed with water (twice) and brine, driedover magnesium sulfate, filtered and concentrated under reducedpressure. The residue was subjected to a column chromatography on asilica gel (hexane/ethyl acetate 5:1) and the resultant crystals werewashed with hexane to obtain 4-cyano-α,α-dimethylbenzeneacetonitrile(4.76 g, yield: 52%).

[2829]¹H NMR (CDCl₃) δ1.75 (6H, s), 7.61 (2H, d, J=8.6 Hz), 7.71 (2H, d,J=8.6 Hz).

[2830] Using this and by the method similar to that in EXAMPLE 17, thetitle, compound was obtained. Yield: 7.8%.

[2831] Melting point: 122-123° C. (duisopropyl ether-hexane).

[2832]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.33 (6H, s), 1.74 (6H, s), 2.22(2H, s), 2.69 (2H, s), 3.93 (3H, s), 6.62 (1H, s), 7.43 (2H, d, J=8.8Hz), 7.50 (2H, d, J=8.8 Hz).

Example 270

[2833]α,α-Dimethyl-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzeneacetamide

[2834] After separating a nitrile form by a column chromatography inEXAMPLE 269 followed by elution with ethyl acetate, the resultantcrystals were washed with diusopropyl ether to obtain the titlecompound. Yield: 9.6%.

[2835] Melting point: 180-182° C.

[2836]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.31 (6H, s), 1.62 (6H, s), 2.21(2H, s), 2.69 (2H, s), 3.93 (3H, s), 5.17 (2H, br s), 6.62 (1H, s), 7.42(4H, s).

Example 271

[2837]α,α-Dimethyl-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzeneaceticacid ethyl ester

[2838] The title compound was obtained fromα,α-Dimethyl-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[t2,3-h]isoquinolin-1-yl)benzeneacetonitrileby the method similar to that in EXAMPLE 241. Yield: 43%.

[2839] Melting point: 150-151° C. (hexane).

[2840]¹H NMR (CDCl₃) δ1.16 (3H, t, J=7.0 Hz), 1.24 (6H, s), 1.30 (6H,s), 1.57 (6H, s), 2.19 (2H, s), 2.68 (2H, s), 3.92 (3H, s), 4.10 (2H, q,J=7.0 Hz), 6.60 (1H, s), 7.34 (4H, s).

Example 272

[2841]N,α,α-Trimethyl-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzeneacetamide

[2842] The title compound was obtained fromα,α-Dimethyl-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzeneacetamideand iodomethane by the method similar to that in EXAMPLE 190. Yield:31%.

[2843] Melting point: 160-162° C. (hexane-diethyl ether).

[2844]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.31 (6H, s), 1.60 (6H, s), 2.20(2H, s), 2.69 (3H, d, J=4.6 Hz), 2.69 (2H, s), 3.93 (3H, s), 5.10 (1H,br s), 6.62 (1H, s), 7.39 (4H, s).

Example 273

[2845]N-[2-Methyl-2-[4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]propanoyl]glycineethyl ester

[2846] Ethyl bromoacetate (0.23 mL, 2.04 mmol) and potassiumtert-butoxide (230 mg, 2.04 mmol) were added to a solution ofα,α-dimethyl-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzeneacetamide(782 mg, 1.85 mmol) in N,N-dimethylformamide (7 mL). and the mixture wasstirred at room temperature for 2 hours. Water was poured into thereaction mixture, which was extracted twice with ethyl acetate. Thecombined organic layer was washed twice with water and with brine, driedover sodium sulfate, filtered and concentrated under reduced pressure.The residue was subjected to a column chromatography on a basic silicagel (hexane/ethyl acetate 3:1 followed by ethyl acetate) and theresultant crystals were washed with diethyl ether-hexane to obtain thetitle compound (63 mg, yield; 6.7%).

[2847] Melting point: 133-138° C.

[2848]¹H NMR (CDCl₃) δ1.24 (6H, s), 1.26 (3H, t, J=7.1 Hz), 1.32 (6H,s), 1.61 (6H, s), 2.25 (2H, s), 2.68 (2H, s), 3.92 (3H, s), 3.93 (2H, d,J=5.2 Hz), 4.15 (2H, q, J=7.1 Hz), 5.67 (1H, br s), 6.61 (1H, s), 7.42(4H, s).

Example 274

[2849]α,α-Dimethyl-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzeneaceticacid ethyl ester hydrochloride

[2850] By the method similar to that in EXAMPLE 17 and starting from3-cyano-α,α-dimethylbenzeneacetic acid ethyl ester, a free base of thetitle compound was obtained ¹H NMR (CDCl₃) δ1.16 (3H, t, J=7.0 Hz), 1.25(6H, br s), 1.30 (6H, s), 1.55 (6H, s), 2.15 (2H, s), 2.70 (2H, s), 3.92(3H, s), 4.10 (2H, q, J=7.0 Hz), 6.61 (1H, s), 7.22-7.38 (4H, m).

[2851] This was dissolved in ethyl acetate, combined with 4 M hydrogenchloride/ethyl acetate solution, concentrated under reduced pressure,and crystallized from ethyl acetate to obtain. the title compound.Yield: 12%.

[2852] Melting point: 143-145° C.

[2853]¹H NMR (DMSO-d) δ1.10 (3H, t, J=7.0 Hz), 1.21 (6H, s), 1.41 (3H,s), 1.45 (3H, s), 1.53 (6H, s), 2.10 (2H, s), 3.14 (2H, s), 3.94 (3H,s), 4.08 (2H, q, J=7.0 Hz), 7.09 (1H, s), 7.48-7.65 (4H, m).

Example 275

[2854]α,α-Dimethyl-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzeneaceticacid sodium salt

[2855] 5 M aqueous solution of sodium hydroxide (4 mL) was added to asolution ofα,α-dimethyl-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzeneaceticacid ethyl ester (370 mg, 0.823 mmol) andα,α-Dimethyl-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzeneaceticacid ethyl ester hydrochloride (1.54 g, 3.17 mmol) in ethanol (8 mL) andthe mixture was stirred at 70° C. for 7 hours. After distilling ethanoloff under reduced pressure, the residue was combined with water-diethylether and the precipitated crystals were recovered by filtration toobtain the title compound (423 mg, yield: 24%).

[2856] Melting point: 153-155° C.

[2857]¹H NMR (DMSO-d() δ1.13 (6H, s), 1.20 (6H, s), 1.34 (6H, s), 2.22(2H, s), 2.62 (2H, s), 3.80 (3H, s), 6.78 (1H, s), 7.12-7.41 (4H, m).

Example 276

[2858]α,α-Dimethyl-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzeneaceticacid

[2859] A mother liquor after filtration of the sodium salt in Example275 was concentrated under reduced pressure. The residue was combinedwith water, adjusted at pH 5.5 with 2 M hydrochloric acid, and extractedtwice with tetrahydrofuran. The combined organic layer was dried oversodium sulfate, filtered and concentrated under reduced pressure toobtain the title compound. Yield: 49%.

[2860] Amorphous.

[2861]¹H NMR (CDCl₃) δ1.27 (6H, s), 1.32 (6H, br 5), 1.47 (6H, s), 2.08(2H, s), 2.74 (2H, br s), 3.92 (3H, s), 6.60 (1H, s), 7.12-7.37 (4H, m).

Example 277

[2862]N,α,α-Trimethyl-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzeneacetamidehydrochloride

[2863] The title compound was obtained fromα,α-dimethyl-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2.3-h]isoquinolin-1-yl)benzeneaceticacid by the method similar to that in EXAMPLE 206. Yield: 55%.

[2864] Amorphous.

[2865]¹H NMR (DMSO-d₆) δ1.22-1.50 (18H, m), 2.02-2.24 (2H, m), 2.55 (3H,d, J=4.4 Hz), 2.97-3.40 (2H, m), 3.94 (3H, s), 7.09 (1H, s), 7.45-7.69(4H, m), 8.06 (1H, br s).

Example 278

[2866]α,α-Dimethyl-N-(4-pyridinylmethyl)-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzeneacetamidedihydrochloride

[2867] The title compound was obtained fromα,α-dimethyl-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzeneaceticacid and 4-(aminomethyl)pyridine by the method similar to that inEXAMPLE 206. Yield: 49%.

[2868] Amorphous.

[2869]¹H NMR (DMSO-d4) δ1.17 (6H, s), 1.45 (6H, s), 1.60 (6H, s),2.05-2.25 (2H, m), 3.05-3.30 (2H, m), 3.95 (3H, s), 4.33-4.50 (2H, m),7.10 (1H, s), 7.49-7.69 (7H, m), 8.48-8.58 (1H, m), 8.68-8.71 (2H, m),9.05 (1H, br s).

Example 279

[2870]1-[4-(Bromomethyl)phenyl]-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinoline

[2871] The title compound was obtained from 4-cyanobenzyl bromide by themethod similar to that in EXAMPLE 17. Yield: 27%.

[2872] Amorphous.

[2873]¹H NMR (CDCl₃)δ1.24 (6H, s), 1.32 (6H, s), 2.21 (2H, s), 2.68 (2H,s), 3.92 (3H, s), 4.53 (2H, s), 6.60 (1H, s), 7.34-7.42 (4H, m).

Example 280

[2874]4-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzeneacetonitrlle

[2875] The title compound was obtained from1-[4-(bromomethyl)phenyl]-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolineby the method similar to that in EXAMPLE 240. Yield: 13%.

[2876] Melting point: 182-184° C. (hexane-diethyl ether).

[2877]¹H NMR (CDCl₃) δ1.24 (6H, s), 1.33 (6H, s), 2.21 (2H, s), 2.69(2H, s), 3.80 (2H, s), 3.93 (3H, s), 6.62 (1H, s), 7.36 (2H, d, J=8.3Hz), 8.44 (2H, d, J=8.3 Hz).

Example 281

[2878]4-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzeneaceticacid ethyl ester hydrochloride While cooling in ice, conc. sulfuric acid(0.18 mL, 3.58 mmol) was added to a solution of4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzeneacetonitrile(671 mg, 1.19 mmol) in ethanol (7 mL) and the mixture was heated underreflux for 24 hours. Ice water was poured into the reaction mixture,which was washed with diisopropyl ether and the aqueous layer wasneutralized with conc. aqueous ammonia, and extracted twice with ethylacetate. The combined organic layer was washed with water and brine,dried over sodium sulfate, filtered and concentrated under reducedpressure. The residue was subjected to a column chromatography on abasic silica gel (hexane/ethyl acetate 10:1 followed by 5:1) followed bya column chromatography on a silica gel (hexane/ethyl acetate 3:1) toobtain a free base of the title compound. This was dissolved in ethylacetate, combined with 4 M hydrogen chloride/ethyl acetate solution,concentrated under reduced pressure and crystallized from ethylacetate-ethanol to obtain the title compound (406 mg, yield: 50%).

[2879] Melting point: 104-106° C.

[2880]¹H NMR (DMSO-d4) δ1.19 (3H, t, J=7.2 Hz), 1.22 (6H, s), 1.44 (6H,s), 2.20 (2H, s), 3.16 (2H, s), 3.86 (2H, s), 3.94 (3H, s), 4.10 (2H, q,J=7.2 Hz), 7.10 (1H, s), 7.52-7.62 (4H, m), 12.60 (1H, br s).

Example 282

[2881]2-[[[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]amino]methylene]-1,3-propanedioicacid diethyl ester

[2882] 2-(Chloromethylene)malonic acid diethyl ester (1.0 g, 4.84 mmol)and triethylamine (0.72 mL, 5.18 mmol) were added to a solution of3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine(1.76 g, 5.03 mmol) in toluene (3.5 mL) and stirred at 85° C. for 3hours. Water was poured into the reaction mixture, which was extractedtwice with ethyl acetate. The combined organic layer was washed withbrine, dried over sodium sulfate, filtered, and concentrated underreduced pressure. The residue was subjected to a column chromatographyon a basic silica gel (hexane/ethyl acetate 10:1. followed by 5:1) andcrystallized from diethyl ether-hexane to obtain the title compound (905mg, yield: 36%).

[2883] Melting point: 115-117° C.

[2884] 1H NMR (CDCl₃) δ1.33 (12H, s), 1.33 (3H, t, J=7.2 Hz), 1.38 (3H,t, J=7.2 Hz), 2.24 (2H, s), 2.70 (2H, s), 3.93 (3H, s), 4.25 (2H, q,J=7.2 Hz), 4.31 (2H, q, J=7.2 Hz), 6.62 (1H, s), 7.10-7.41 (4H, m), 8.57(1H, d, J=13.7 Hz), 11.09 (1H, d, J=13.7 Hz).

Example 283

[2885]N-Ethyl-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine

[2886] Triethylamine (0.50 mL, 3.55 mmol) was added to a solution of3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine(1.21 g, 3.45 mmol) and (Z)-3-iodo-2-propenamide (654 mg, 3.32 mmol) intoluene (2.5 mL) and the mixture was stirred at 60° C. for 2. hours andthen at 80° C. for 6 hours. The reaction mixture was extracted with 2 Mhydrochloric acid, and the aqueous layer was neutralized with conc.aqueous ammonia, and extracted twice with ethyl acetate. The combinedorganic layer was washed with. brine, dried over sodium sulfate,filtered, and concentrated under reduced pressure. The residue wassubjected to a column chromatography on a basic silica gel (hexane/ethylacetate 5:1 followed by 3:1) and crystallized from hexane to obtain thetitle compound (178 mg, yield: 14%).

[2887] Melting point: 109-111° C.

[2888]¹H NMR (CDCl₃) δ1.23 (6H, s), 1.24 (3H, t, J=7.2 Hz), 1.32 (6H,s), 2.35 (2H, s), 2.67 (2H, s), 3.16 (2H, q, J=7.2 Hz), 3.66 (1H, br s),3.91 (3H, s), 6.59 (1H, s), 6.63-6.69 (3H, m), 7.11-7.19 (1H, m).

Example 284

[2889]N-[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-3-pyridinamine

[2890] Tris(dibenzylideneacetone)dipalladium (0) (65 mg, 0.0707 mmol)was added to a suspension of3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine(1.23 g, 3.46 mmol), 3-bromopyridine (0.32 mL, 3.43 mmol),sodium-tert-butoxide (411 mg, 4.81 mmol) and2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (98 mg, 0.141 mol) intoluene (30.5 mL) and the mixture was stirred at 110° C. for 24 hours.Water was poured into the reaction mixture, which was extracted twicewith ethyl acetate. The combined organic layer was washed with brine,dried over magnesium sulfate, filtered and concentrated under reducedpressure. The residue was subjected to a column chromatography on abasic silica gel (hexane/ethyl acetate 3:1 followed by 1:1) andcrystallized from hexane-diethyl ether to obtain the title compound (796mg, yield: 54%).

[2891] Melting point: 204-205° C.

[2892]¹H NMR (CDCl₃) δ1.24 (6H, s), 1.34 (6H, s), 2.34 (2H, s), 2.69(2H, s), 3.92 (3H, s), 5.79 (1H, s), 6.61 (1H, s), 6.97 (1H, d, J=7.6Hz), 7.11-7.43 (5H, m), 8.11 (1H, dd, J=4.8, 1.4 Hz), 8.40 (1H, d, J=2.8Hz).

Example 285

[2893]N-(3-Pyridinyl)-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]acetamide

[2894] While cooling in ice, sodium hydride (66% dispersion in oil) (57mg, 1.57 mmol) was added to a solution ofN-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-3-pyridinamine(513 mg, 1.20 mmol) in N,N-dimethylformamide (5 mL) and the mixture wasstirred at room temperature for 20 minutes under reduced pressure. Andthen, while cooling in ice, acetyl chloride (0.11 mL, 1.50 mmol) wasadded thereto and the mixture was stirred at room temperature for 15hours. Ice water was poured into the reaction mixture, which wasextracted twice with ethyl acetate. The combined organic layer waswashed with water (twice) and brine, dried over sodium sulfate, filteredand concentrated under reduced pressure. The residue was subjected to acolumn chromatography on a basic silica gel (hexane/ethyl acetate 1:1followed by 1:2) to obtain a mixture of the starting material and thetitle compound. This was subjected to the similar reactions and work-upsand subjected to a column chromatography on a silica gel (hexane/ethylacetate 3:1) and crystallized from diethyl ether to obtain the titlecompound (176 mg, yield: 31%).

[2895] Melting point: 157-158° C.

[2896]¹H NMR (CDCl₃) δ1.23 (6H, s), 1.24 (6H, s), 2.09 (5H, s), 2.68(2H, s), 3.91 (3H, s), 7.09 (1H, s), 7.25-7.67 (6H, m), 8.45-8.53 (2H,m).

Example 286

[2897]N-Methyl-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-3-pyridinaminetrihydrochloride

[2898] By the method similar to that in EXAMPLE 285 and usingiodomethane, a free base of the title compound was obtained. This wasdissolved in ethyl acetate, combined with 4 M hydrogen chloride/ethylacetate solution and concentrated under reduced pressure to obtain thetitle compound. Yield; 74%.

[2899] Amorphous.

[2900]¹H NMR (DMSO-d₆) δ1.21 (6H, s), 1.46 (6H, s), 2.30 (2H, s), 3.16(2H, s), 3.43 (3H, s), 3.94 (3H, s), 7.10 (1H, s), 7.45-7.86 (6H, m),8.27-8.29 (2H, m).

Example 287

[2901]3-Pyridinyl[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]carbamicacid ethyl ester dihydrochloride

[2902] By the method similar to that in EXAMPLE 190 and starting fromN-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-3-pyridinamineand ethyl chloroformate, a free base of the title compound was obtained.This was dissolved in ethyl acetate, combined with 4 M hydrogenchloride/ethyl acetate solution and concentrated, under reduced pressureto -obtain the title compound. Yield: 29%.

[2903] Amorphous.

[2904]¹H NMR (DMSO-d₆) δ1.15 (3H, t, J=7.0 Hz), 1.19 (6H, s), 1.41(3H,s), 1.48 (3H, s), 1.98-2.28 (2H, m), 3.00-3.30 (2H, m), 3.93 (3H, s),4.15 (2H, q, J=7.0 Hz), 7.09 (1H, s), 7.53-7.74 (5H, m), 7.95 (1H, d,J=8.0 Hz), 8.52 (1H, d, J=3.6 Hz), 8.67 (1H, d, J=2.2 Hz), 12.79 (1H, brs).

Example 288

[2905]N-(3-Pyridinyl)-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]urea

[2906] Chlorosulfonyl isocyanate (0.075 mL, 0.865 mmol) was added to asolution ofN-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-3-pyridinamine(336 mg, 0.786 mmol) in tetrahydrofuran (3 mL) and the mixture wasstirred at room temperature for 6 hours. Acetic acid (1 mL) and water(0.5 mL) were added to the reaction mixture and the mixture was stirredat room temperature further for 3 hours. The reaction mixture wasneutralized with 5 M aqueous solution of sodium hydroxide and extractedtwice with ethyl acetate. The combined organic layer was washed withbrine, dried over sodium sulfate, filtered, and concentrated underreduced pressure. The residue was subjected to a column chromatographyon a basic silica gel (hexane/ethyl acetate 1:2 followed by ethylacetate) and crystallized from hexane-ethyl acetate to obtain the titlecompound (177 mg, yield: 48%).

[2907] Melting point: 168-169° C.

[2908]¹H NMR (CDCl₃) δ1.24 (6H, br s), 1.26 (6H, s), 2.14 (2H, s), 2.69(2H, s), 3.91 (3H, s), 4.74 (2H, br s), 6.60 (1H, s), 7.24-7.31 (2H, m),7.39-7.53 (3H, m), 7.70-7.78 (1H, m), 8.40 (1H, dd, J=4.6, 1.3 Hz), 8.49(1H, d, J=2.0 Hz).

Example 289

[2909]N-Phenyl-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine

[2910] Calcium carbonate (570 mg, 1.75 mmol), palladium (II) acetate(8.4 mg, 0.0375 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl(35 mg, 0.0563 mmol) were added to a solution of1-(3bromophenyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinoline(517 mg, 1.25 mmol) and aniline (0.04 mL, 1.50 mmol) in toluene (2.5 mL)and the mixture was stirred at 100° C. for 24 hours. Ice water waspoured into the reaction mixture, which was extracted twice with ethylacetate. The combined organic layer was washed with brine, dried oversodium sulfate, filtered, and concentrated under reduced pressure. Theresidue was subjected to a column chromatography on a basic silica gel(hexane/ethyl acetate 10:1 followed by 3:1) and crystallized fromdiethyl ether to obtain the title compound (226 mg, yield: 42%).

[2911] Melting point: 87-88° C.

[2912]¹H NMR (CDCl₃) δ1.24 (6H, s), 1.34 (6H, s), 2.36 (2H, s), 2.68(2H, s), 3.91 (3H, s), 5.74 (1H, s), 6.59 (1H, s), 6.89-7.30 (9H, m).

Example 290

[2913]N-Phenyl-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]acetamidehydrochloride

[2914] Triethylamine (0.18 mL, 1.28 mmol) and acetyl chloride (0.086 mL,1.22 mmol) were added to a solution ofN-phenyl-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine(494 mg, 1.16 mmol) in N,N-dimethylformamide (2 mL) and the mixture wasstirred at room temperature for 10 hours. Ice water was poured into thereaction mixture, which was extracted twice with ethyl acetate. Thecombined organic layer was washed with brine, dried over sodium sulfate,filtered, and concentrated under reduced pressure. The residue wassubjected to a column chromatography on a basic silica gel (hexane/ethylacetate 3:1) to obtain a free base of the title compound. This wasdissolved in ethyl acetate, combined with 4 M hydrogen chloride/ethylacetate solution, concentrated under reduced pressure to obtain thetitle compound (364 mg, yield: 62%).

[2915] Amorphous.

[2916]¹H NMR (DMSO-d₆) δ1.56 (6H, s), 1.37 (3H, s), 1.51 (3H, s), 1.95(3H, s), 2.50 (2H, s), 3.26 (2H, s), 3.93 (3H, s), 7.09 (1H, s),7.30-7.80 (9H, m), 12.70 (1H, s).

Example 291

[2917]1-(3-Bromophenyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-4-furo[2,3-h]isoquinolinolhydrochloride

[2918] N-Bromosuccinimide (773 mg, 4.34 mmol) and2,2′-azobis(isobutyronitrile) (79 mg, 0.483 mmol) were added to asolution of1-(3bromophenyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinoline(2.00 g, 4.83 mmol) in carbon tetrachloride (20 mL) and the mixture wasstirred at 60° C. for 6 hours. The reaction mixture was extracted twicewith 2 M hydrochloric acid, and the combined aqueous layer wasneutralized with conc. aqueous ammonia and extracted twice with ethylacetate. The combined organic layer was washed with water and brine,dried over sodium sulfate, filtered and concentrated under reducedpressure. The residue was subjected to a column chromatography on asilica gel (hexane/ethyl acetate 5:1 followed by 1:2) to obtain a freebase of the title compound.

[2919]¹H NMR (CDCl₃) δ1.25 (3H, s), 1.30 (3H, s), 1.35 (3H, s), 1.36(3H, s), 2.26 (2H, s), 3.96 (3H, s), 4.48 (1H, s), 6.96 (1H, s),7.22-7.39 (2H, m), 7.50-7.62 (2H, m).

[2920] This was dissolved in ethyl acetate, combined with 4 M hydrogenchloride/ethyl acetate solution and crystallized from ethyl acetate toobtain the title compound (630 mg, yield: 31%).

[2921] Melting point: 190-192° C.

[2922]¹H NMR (DMSO-d₆) δ1.24 (3H, s), 1.28 (3H, s), 1.34 (3H, s), 1.41(3H, s), 2.26 (2H, s), 3.97 (3H, s), 4.56 (1H, br s), 6.17 (1H, s), 7.24(1H, s), 7.59-7.62 (2H, m), 7.95-7.99 (2H, m).

Example 292

[2923]N-[3′-(3,4,8,9-Tetrahydro-4-hydroxy-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-3-yl]acetamide

[2924] The title compound was obtained from1-(3bromophenyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-4-furo[2,3-h]isoquinolinoland 3-acetamidobenzeneboronic acid by the method similar to that inEXAMPLE 254. Yield: 64%.

[2925] Amorphous.

[2926]¹H NMR (CDCl₃) δ1.25 (3H, s), 1.30 (6H, s), 1.33 (3H, s), 2.18(3H, s), 2.26 (2H, s), 3.97 (3H, s), 4.45 (1H, s), 6.96 (1H, s),7.23-7.63 (8H, m), 7.72 (1H, br s).

Example 293

[2927]N-[3′-(3,4,8,9-Tetrahydro-4-hydroxy-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-3-yl]acetamidehydrochloride

[2928] The title compound was obtained fromN-[3′-(3,4,8,9-tetrahydro-4-hydroxy-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-3-yl]acetamideby the method similar to that in EXAMPLE 212. Yield: 88%.

[2929] Amorphous.

[2930]¹H NMR (DMSO-d₆) δ1.21 (6H, s), 1.37 (3H, s), 1.45 (3H, s), 2.07(3H, s), 2.32 (2H, s), 3.98 (3H, s), 4.61 (1H, br s), 6.18 (1H, br s),7.26 (1H, s), 7.42-8.06 (8H, m), 10.19 (1H, s), 12.67 (1H, br s).

Example 294

[2931]N-[3′-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-4-oxofuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-3-yl]acetamide

[2932] Manganese dioxide (1.04 g, 12.0 mmol) was added to a solution ofN-[3′-(3,4,8,9-tetrahydro-4-hydroxy-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-3-yl]acetamide(290 mg, 0.598 mmol) in chloroform (5 mL) and the mixture was stirred atroom temperature for 6 hours. Inorganics were filtered off and thefiltrate was concentrated under reduced pressure. The residue wassubjected to a column chromatography on a silica gel (hexane/ethylacetate 1:1 followed by 1:2) and crystallized from hexane-ethyl acetateto obtain the title compound (209 mg, yield: 72%).

[2933] Melting point: 210-212° C.

[2934]¹H NMR (CDCl₃) δ1.34 (6H, s), 1.56 (6H, s), 2.20 (3H, s), 2.26(2H, s), 4.00 (3H, s), 7.27-7.69 (8H, m), 7.84 (1H, s).

Example 295

[2935]5-[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2-pyridinamine

[2936] A solution of sodium carbonate (198 mg, 1.86 mmol) in water (1mL) and tetrakis(triphenylphosphine)palladium(0) (55 mg, 0.0475 mmol)were added to a solution of N-(5bromo-2-pyridinyl)acetamide (243 mg,1.13 mmol) and 3-cyanophenylboronic acid (249 mg, 1.70 mmol) in1,2-dimethoxyethane (2 mL) and ethanol (1 mL) and the mixture wasstirred at 80° C. for 15 hours. Water was poured into the reactionmixture, which was extracted twice with tetrahydrofuran. The combinedorganic layer was washed with brine, dried over sodium sulfate,filtered, and concentrated under reduced pressure. The resultantcrystals were washed with diethyl ether to obtainN-[5-(3-cyanophenyl)-2-pyridinyl]acetamide (205 mg, yield: 77%).

[2937]¹H NMR (CDCl₃) δ2.25 (3H, s), 7.54-7.92 (5H, m), 8.02 (1H, br s),8.32 (1H, d, J=8.0 Hz), 8.48 (1H, d, J=2.2 Hz).

[2938] Using this and by the method similar to that. in EXAMPLE 17, thetitle compound was obtained. Yield: 11%.

[2939] Melting point: 165-168° C. (diethyl ether).

[2940]¹H NMR (CDCl₃) δ1.27 (6H, s), 1.30 (6H, s), 2.26 (2H, s), 2.72(2H, s), 3.93 (3H, s), 4.50 (2H, s), 6.57 (1H, dd, J=8.4, 0.8 Hz), 6.63(1H, s), 7.32-7.56 (4H, m), 7.70 (1H, dd, J=8.4, 2.4 Hz), 8.34 (1H, d,J=1.8 Hz).

Example 296

[2941]N-[5-[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2-pyridinyl]acetamide

[2942] From a mixture of5-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2-pyridinamineobtained by the column chromatography in EXAMPLE 295 andN-[5-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2-pyridinyl]acetamideand by the method similar to that in EXAMPLE 222, the title compound wasobtained. Yield: 8.9%.

[2943] Melting point: 208-209° C. (diethyl ether).

[2944]¹H NMR (CDCl₃) δ1.27 (6H, s), 1.30 (6H, s), 2.23 (3H, s), 2.26(2H, s), 2.72 (2H, s), 3.93 (3H, s), 6.63 (1H, s), 7.25 (1H, d, J=8.4Hz), 7.38-7.58 (4H, m), 7.91-7.96 (2H, m), 8.51 (1H, d, J=1.4 Hz).

Example 297

[2945]N-[5-[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2-pyridinyl]methanesulfonamidehydrochloride

[2946] By the method similar to that in EXAMPLE 222 and starting from5-13-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl-2-pyridinylamineand methanesulfonyl chloride, a free.base of the title compound wasobtained. This -was dissolved in ethyl acetate, combined with 4 Mhydrogen chloride/ethyl acetate solution, and concentrated under reducedpressure to obtain the title compound. Yield: 54%.

[2947] Amorphous.

[2948]¹H NMR (DMSO-d₆) δ1.21 (6H, s), 1.45 (3H, s), 1.52 (3H, s), 2.26(2H, s), 3.00-3.40 (5H, m), 3.95 (3H, s), 7.13-7.15 (2H, m), 7.58-7.78(2H, m), 8.02-8.52 (6H, m).

Example 2986-(Ethylthio)-3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolinehydrochloride

[2949] By the method similar to that in EXAMPLE 17 and starting from7-(ethylthio)-2,3-dihydro-2,2-dimethyl-5-(2-methyl-1-propenyl)benzofuranand benzonitrile, a free base of the title compound was, obtained. Thiswas dissolved in ethyl acetate, combined with 4 M hydrogenchloride/ethyl acetate solution, and concentrated under reduced pressureto obtain the title compound. Yield: 32%.

[2950] Amorphous.

[2951]¹H NMR (DMSO-d) δ1.23 (6H, s), 1.32 (3H, t, J=7.5 Hz), 1.45 (6H,s), 2.19 (2H, s), 3.12 (2H, q₅ J=7.5 Hz), 3.17 (2H, s), 7.23 (1H, s),7.63-7.80 (5H, m).

Example 299

[2952]N-(4-Pyridinylmethyl)-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenesulfonamidedihydrochloride

[2953] 4-(Aminomethyl)pyridine (851 mg, 7.87 mmol) was dissolved inpyridine (2 mL) and, while cooling in ice, 4-cyanobenzenesulfonylchloride (1.75 g, 8.66 mmol) was added and the mixture was stirred atroom temperature for 2 hours. The reaction mixture was combined with 2 Mhydrochloric acid with cooling in ice, and washed with diethyl ether.The aqueous layer was adjusted at pH 8 with 5 M aqueous solution ofsodium hydroxide and extracted twice with ethyl acetate. The combinedorganic layer was washed with brine. dried over sodium sulfate.filtered, and concentrated under reduced pressure. The residue wassubjected to a column chromatography on a basic silica gel (ethylacetate) to obtain 4-cyano-N-(4-pyridinylmethyl)benzenesulfonamide (674mg, yield: 31%).

[2954]¹H NMR (CDCl₃+DMSO-d₆2 drops) δ4.12 (2H, d, J=5.4 Hz), 7.20 (2H,dd, J=4.4, 1.4 Hz), 7.74-7.80 (2H, m), 7.94-8.00 (2H, m), 8.08 (1H, brs), 8.50 (2H, dd, J=4.4, 1.8 Hz).

[2955] Using this and by the method similar to that in EXAMPLE 17, afree base of the title compound was obtained. This was dissolved inethyl acetate, combined with 4 M hydrogen chloride/ethyl acetatesolution, concentrated under reduced pressure and crystallized fromethanol-ethyl acetate to obtain the title compound. Yield: 18%.

[2956] Amorphous.

[2957]¹H NMR (DMSO-d₆) δ1.24 (6H, s), 1.48 (6H, s), 2.16 (2H, s), 3.19(2H, s), 3.95 (3H, s), 4.34 (2H, d, J=8 6.0 Hz), 7.12 (1H, s), 7.83-7.89(4H, m), 8.08 (2H, d, J=8.4 Hz), 8.82 (2H, d, J =6.6 Hz), 9.07 (1H, t,J=6.0 Hz).

Example 300

[2958]N-Methyl-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenesulfonamide

[2959] Methylamine hydrochloride (1.05 g, 15.6 mmol) was dissolved inpyridine (4 mL), 4-cyanobenzenesulfonyl-chloride (3.30 g, 16.4 mmol) wasadded thereto with cooling in ice, and the mixture was stirred at roomtemperature for 2 hours. The reaction mixture was combined with icewater, acidified with 1 M hydrochloric acid, and extracted twice withethyl acetate. The combined organic layer was washed with water andbrine, dried over magnesium sulfate, filtered and concentrated underreduced pressure. The residue was subjected to a column chromatographyon a silica gel (hexane/ethyl acetate 3:1 followed by 1:1), and theresultant crystals were washed with diethyl ether to obtain4-cyano-N-methylbenzenesulfonamide (1.54 g, yield: 56%).

[2960]¹H NMR (CDCl₃) δ2.72 (3H, d, J=5.2 Hz), 4.50 (1H, q, J=5.2 Hz),7.84 (2H, dd, J=6.6, 1.8 Hz), 7.99 (2H, dd, J=6.6, 1.8 Hz).

[2961] The title compound was obtained from this by the method similarto that in EXAMPLE 17. Yield: 26%.

[2962] Melting point: 146-148° C. (methanol-diethyl ether).

[2963]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.32 (6H, s), 2.17 (2H, s), 2.65(3H, d, J=5.3 Hz), 2.71 (2H, s), 3.93 (3H, s), 4.43 (1H, q, J=5.3 Hz),6.63 (1H, s), 7.57 (2H, d, J=8.3 Hz), 7.89 (2H, d, J=8.3 Hz).

Example 301

[2964]N-(2-Amino-2-oxoethyl)-N-methyl-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenesulfonamide

[2965] The title compound was obtained fromN-methyl-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenesulfonamideand 2bromoacetamide by the method similar to that in EXAMPLE 190. Yield:35%.

[2966] Melting point: 115-117° C. (ethyl acetate-diethyl ether).

[2967]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.33 (6H, s), 2.14 (2H, s), 2.71(2H, s), 2.84 (3H, s), 3.63 (2H, s), 3.93 (3H, s), 5.57 (1H, br s), 6.57(1H, br s), 6.64 (1H, s), 7.62 (2H, d, J=8.4 Hz), 7.84 (2H, d, J=8.4Hz).

Example 302

[2968]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-(6-quinolinyl)furo[2,3-h]isoquinolinedihydrochloride

[2969] A free base of the title compound was obtained from6-quinolinecarbonitrile by the method similar to that in EXAMPLE 28.This was dissolved in ethyl acetate, combined with 4 M hydrogenchloride/ethyl acetate solution, concentrated under reduced pressure,and crystallized from ethanol-ethyl acetate to obtain the titlecompound. Yield: 37%.

[2970] Melting point: 182-184° C.

[2971]¹H NMR (DMSO-d₆) δ1.17 (6H, s), 1.50 (6H, s), 2.18 (2H, s),3.05-3.35 (2H, m), 3.87 (3H, s), 7.15 (1H, s), 7.86 (1H, dd, J=8.6, 4.4Hz), 8.02 (1H, dd, J=8.8, 1.8 Hz), 8.36 (1H, d, J=8.8 Hz), 8.51 (1H, s),8.78 (1H, d, J=8.0 Hz), 9.21 (1H, dd, J=4.4, 1.4 Hz).

Example 303.

[2972]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-(7-quinolinyl)furo[2,3-h]isoquinoline

[2973] A solution of 7-quinolinecarboxamide (1.21 g, 7.03 mmol) inchloroform (8 mL) was treated dropwise with phosphorus oxychloride (3.28mL, 35.1 mmol), and stirred at 90° C. for 3 hours. The reaction mixturewas poured into ice water, neutralized with conc. aqueous ammonia andextracted twice with ethyl acetate. The combined organic layer waswashed with water and brine, dried over sodium sulfate, and concentratedunder reduced pressure to obtain 7-quinolinecarbonitrile (984 mg, yield:72%).

[2974]¹H NMR (CDCl₃) δ7.57 (1H, dd, J=8.5, 4.1 Hz), 7.72 (1H, dd, J=8.4,1.4 Hz), 7.94 (1H, d, J=8.4 Hz), 8.20-8.27 (1H, m), 8.50 (1H, s), 9.06(1H, dd, J=4.2, 1.6 Hz).

[2975] The title compound was obtained from this by the method similarto that in EXAMPLE 28. Yield: 48%.

[2976] Melting point: 172-174° C. (diethyl ether).

[2977]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.29 (6H, s), 2.19 (2H, s), 2.74(2H, s), 3.94 (3H, s), 6.65 (1H, s), 7.43 (1H, dd, J=8.2, 4.2 Hz), 7.61(1H, dd, J=8.2, 1.6 Hz), 7.85 (1H, d, J=8.4 Hz), 8.15-8.21 (2H, m), 8.95(1H, dd, J=4.2, 1.6 Hz).

Example 304

[2978]N-Methyl-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine

[2979] The title compound was obtained from 3-(methylamino)benzonitrileby the method similar to that in EXAMPLE 28. Yield: 22%.

[2980] Melting point: 105-107° C. (diethyl ether-hexane).

[2981]¹H NMR (CDCl₃) 6-1.24 (6H, s), 1.32-(6H, s), 2.35 (2H, s), 2.68(2H, s), 2.84 (3H, s), 3.73 (1H, br s), 3.92 (3H, s), 6.59 (¹H, s),6.63-6.70 (3H, m), 7.13-7.21 (1H, m).

Example 305

[2982]3,4,8,9-Tetrahydro-3,3,6,8,8-pentamethyl-1-phenylfuro[2,3-h]isoqulnolinehydrochloride

[2983] Phosphorus oxychloride (1.10 mL, 11.8 mmol) was added to asolution of2,3-dihydro-2,2,7-trimethyl-5-(2-methyl-1-propenyl)benzofuran (1.02 g,1.94 mmol) and benzamide (1.14 g, 9.43 mmol) in toluene (10 mL) and themixture was stirred at 60° C. for 2 hours, and then at 90° C. for 3hours. The reaction. mixture was poured into water, and the aqueouslayer was separated, neutralized by 5 M aqueous solution of sodiumhydroxide, and extracted twice with ethyl acetate. The combined organiclayer was washed with brine, dried over magnesium sulfate, filtered andconcentrated under reduced pressure. The residue was subjected to acolumn chromatography on a basic silica gel (hexane/ethyl acetate 100:1followed by 10:1) to obtain a free base of the title compound. This wasdissolved in hexane, combined with 4 M hydrogen chloride/ethyl acetatesolution, and concentrated under reduced pressure to obtain the titlecompound (65 mg, yield: 3.9t).

[2984] Amorphous.

[2985]¹H NMR (DMSO-d₆) δ1.23 (6H, s), 1.43 (6H, s), 2.19 (2H, s), 2.21(3H, s), 3.11 (2H, s), 7.16 (1H, s), 7.64-7.80 (5H, m).

Example 306

[2986]1-(4-Cyclohexylphenyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolinehydrochloride

[2987] A free base of the title compound was obtained from4-cyclohexylbenzonitrile by the method similar to that in EXAMPLE 1.This was dissolved in ethanol, combined with 3.3 M solution of hydrogenchloride/ethanol, and concentrated under reduced pressure. The resultantresidue was crystallized from ethyl acetate to obtain the titlecompound. Yield: 21%.

[2988] Melting point: 213-214° C.

[2989]¹H NMR (CDCl₃) δ1.23-1.54 (12H, m), 1.69-1.96(10H, m), 2.54-2.68(1H, m), 2.28 (2H, s), 3.00 (2H, s), 4.01 (3H, s), 6.74 (1H, s), 7.39(2H, d, J=8.3 Hz), 7.68 (2H, d, J=8.3 Hz).

Example 307

[2990]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-(4-phenoxyphenyl)furo[2,3-h]isoquinolinehydrochloride

[2991] The title compound was obtained from 4-phenoxybenzonitrile by themethod similar to that in EXAMPLE 306. Yield: 19%.

[2992] Melting point: 198-199° C. (ethyl acetate-hexane).

[2993]¹H NMR (CDCl₃) δ1.39 (6H, s), 1.68 (6H, s), 2.40 (2H, s), 3.00(2H, s), 4.02 (3H, s), 6.74 (1H, s), 7.12 (4H, d, J=8.7 Hz), 7.18-7.26(1H, m), 7.42 (2H, t, J=8.2 Hz), 7.75 (2H, d, J=8.7 Hz).

Example 308

[2994]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-(2-naphthyl)furo[2,3-h]isoquinolinehydrochloride

[2995] The title compound was obtained from β-naphthonitrile by themethod similar to that in EXAMPLE 306. Yield: 37%.

[2996] Melting point: 158-160° C. (ethyl acetate).

[2997]¹H NMR (CDCl₃) δ1.29 (6H, s), 1.73 (6H, br s), 2.27 (2H, s), 3.05(2H, br s), 4.03 (3H, s), 6.78 (¹H, s), 7.56-7.70 (3H, m), 7.90-8.09(3H, m), 8.49 (1H, s).

Example 309

[2998]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-[4-(1-piperidinyl)phenyl]furo[2,3-h]isoquinolinehydrochloride

[2999] The title compound was obtained from4-(1-piperidinyl)benzonitrile by the method similar to that in EXAMPLE306. Yield: 18%.

[3000] Melting point: 188-190° C. (ethyl acetate-hexane).

[3001]¹H NMR (CDCl₃) δ1.63 (6H, s), 1.68 (12H, br), 2.58 (2H, s), 2.93(2H, s), 3.42 (4H, br), 4.00 (3H, s), 6.71 (1H, s), 6.93 (2H, d, J=8.4Hz), 7.77 (2H, d, J=8.4 Hz).

Example 310

[3002]2,6-Bis(1,1-dimethylethyl)-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenolhydrochloride

[3003] The title compound was obtained from3,5-bis(1,1-dimethylethyl)-4-hydroxybenzonitrile by the method similarto that in EXAMPLE 306. Yield: 50%.

[3004] Melting point: 211-213° C. (ethyl acetate-hexane).

[3005]¹H NMR (CDCl₃) δ1.50 (18H, s), 1.69 (12H, s), 2.40 (2H, s), 2.98(2H, s), 4.02 (3H, s), 5.90 (1H, s), 6.74 (1H, s), 7.53 (2H, s).

EXAMPLE 311

[3006]3,4,8.9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl--(4-methyl-2-phenyl-1H-imidazol-5-yl)furo[2,3-h]isoquinolinehydrochloride

[3007] The title compound was obtained from4-methyl-2-phenyl-1H-imidazol-5-carbonitrile by the method similar tothat in EXAMPLE 306. Yield: 5%.

[3008] Melting point: 238-240° C. (ethyl acetate).

[3009]¹H NMR (CDCl₃) δ1.35 (6H, br), 1.65 (6H, br), 2.29 (1H, br), 2.63(1H, br), 2.71 (3H, br), 3.08 (2H, br), 4.01 (3H, s), 6.70 (1H, s), 7.22(1H, br), 7.49 (2H, br), 7.90 (2H, br), 8.39 (1H, br).

Example 312

[3010]6-Methyl-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2(1H)-pyridinonehydrochloride

[3011] The title compound was obtained from3-cyano-6-methyl-2(1H)-pyridinone by the method similar to that inEXAMPLE 306. Yield: 53%.

[3012] Melting point: 178-180° C. (ethyl acetate).

[3013]¹H NMR (CDCl₃) δ1.33 (6H, s), 1.51 (6H, s), 1.62 (2H, br), 2.36(3H, s), 2.58 (2H, br), 3.90 (3H, s), 6.06 (1H, d, J=7.3 Hz), 6.59 (1H,s), 7.72 (1H, d, J=7.3 Hz).

Example 313

[3014]1-Cyclopentyl-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolinehydrochloride

[3015] The title compound was obtained from cyclopentanecarbonitrile bythe method similar to that in EXAMPLE 306. Yield: 20%.

[3016] Melting point: 197-198° C. (ethyl acetate).

[3017]¹H NMR (CDCl₃) δ1.57 (6H, s), 1.65 (6H, s), 1.76 (2H, br),2.05-2.30 (4H, m), 2.44-2.57 (2H, m), 2.88 (2H, s), 3.20-3.58 (3H, m),4.00 (3H, s), 6.67 (1H, s).

Example 314

[3018]1-(4-Ethoxyphenyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolinehydrochloride

[3019] The title compound was obtained from 4-ethoxybenzonitrile by themethod similar to that in EXAMPLE 306. Yield: 57%.

[3020] Melting point: 158-160° C. (ethyl acetate).

[3021]¹H NMR (CDCl₃) δ1.37 (6H, s), 1.46 (3H, t, J=7.0 Hz), 1.67 (6H,s), 2.41 (2H, s), 2.99 (2H, s), 4.02 (3H, s), 4.14 (2H, q, J=7.0 Hz),6.74 (1H, s), 7.04 (2H, br d, J=6.1 Hz), 7.75 (2H, br d, J=6.1 Hz).

Example 315

[3022]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-[4-(1-methylethoxy)phenyl]furo[2,3-h]isoquinolinehydrochloride

[3023] The title compound was obtained from4-(1-methylethoxy)benzonitrile by the method similar to that in EXAMPLE306. Yield: 21%.

[3024] Melting point: 130-132° C. (ethyl acetate).

[3025]¹H NMR (CDCl₃) δ1.38 (6H, s), 1.39 (6H, d, J=4.6 Hz), 1.66 (6H,s), 2.43 (2H, s), 2.97 (2H, s), 4.01 (3H, s), 4.65-4.75 (1H, m), 6.72(1H, s), 7.02 (2H, d, J=8.3 Hz), 7.76 (2H, d, J=8.3 Hz).

Example 316

[3026][4-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]methylacetate hydrochloride

[3027] The title compound was obtained from 4-cyanobenzyl acetate by themethod similar to that in EXAMPLE 306. Yield: 24%.

[3028] Melting point: 184-186° C. (ethyl acetate).

[3029]¹H NMR (CDCl₃) δ1.35 (6H, s), 1.68 (9H, br s), 2.30 (2H, s), 3.05(2H, br s), 4.02 (3H, s), 4.74 (2H, s), 6.74 (1H, s), 7.59 (4H, br).

Example 317

[3030]3,4,8,9-Tetrahydro-6-methoxy-1-[4-[2-(4-methoxyphenyl)ethoxy]phenyl]3,3,8,8-tetramethylfuro[2,3-h]isoquinolinehydrochloride

[3031] The title compound was obtained from4-[2-(4-methoxyphenyl)ethoxy]benzonitrile by the method similar to thatin EXAMPLE 306. Yield: 35%.

[3032] Melting point: 198-200° C. (ethyl acetate).

[3033]¹H NMR (CDCl₃) 6.1.37 (6H, s), 1.66 (6H, s), 2.39 (2H, s), 2.98(2H, s), 3.07 (2H, t, J=7.0 Hz), 3.81 (3H, s), 4.01 (3H, s), 4.23 (2H,t, J=7.0 Hz), 6.72 (1H, s), 6.88 (2H, d, J=8.6 Hz), 7.03 (2H, d, J=8.8Hz), 7.22 (2H, d, J=8.6 Hz), 7.72 (2H, d, J=8.8 Hz).

Example 318

[3034]1-Cyclohexyl-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolinehydrochloride

[3035] The title compound was obtained from cyclohexanecarbonitrile bythe method similar to that in EXAMPLE 306. Yield: 28%.

[3036] Melting point: 210-211° C. (ethyl acetate).

[3037]¹H NMR (CDCl₃) δ1.25-1.40 (2H, m), 1.58 (6H, s), 1.65 (6H, s),1.69-1.85 (6H, m), 1.96-2.07 (2H, m), 2.58-2.78 (2H,m), 2.88-3.04 (3H,m), 3.99 (3H, s), 6.67 (1H, s).

Example 319

[3038]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-(2-methylthiazol-4-yl)furo[2,3-h]isoquinoline

[3039] The-title compound was obtained from2-methylthiazol-4-carbonitrile by the method similar to that in EXAMPLE1.

[3040] Yield: 5%.

[3041] Melting point: 127-128° C. (hexane).

[3042]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.37 (6H, s), 2.34 (2H, s), 2.70(2H, s), 2.74 (3H, s), 3.91 (3H, s), 6.59 (1H, s), 7.37 (1H, s).

Example 320

[3043]1-(3-Fluorophenyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolinehydrochloride

[3044] The title compound was obtained from 3-fluorobenzonitrile by themethod similar to that in EXAMPLE 306.

[3045] Yield: 47%.

[3046] Melting point: 198-199° C. (ethyl acetate-hexane). H NMR (CDCl₃)δ1.24 (6H, s), 1.33 (6H, s), 2.24 (2H, s), 2.69 (2H, s), 3.92 (3H, s),6.62 (1H, s), 7.06-7.18 (3H, m), 7.30-7.41 (1H, m).

Example 321

[3047]1-(2,4-Difluorophenyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin

[3048] The title compound was obtained from 2,4-difluorobenzonitrile bythe method similar to that in EXAMPLE 1.

[3049] Yield: 45%.

[3050] Melting point: 143-144° C. (hexane).

[3051]¹H NMR (CDCl₃) δ1.14 (3H, s), 1.32 (3H, s), 1.38 (3H, s), 1.39(3H, s), 2.17 (1H, d, J=15.8 Hz), 2.34 (1H, d, J=15.8 Hz), 2.63 (1H, d,J=15.6 Hz), 2.81 (1H, d, J=15.6 Hz), 3.92 (3H, s), 6.60 (1H, s),6.77-7.00 (2H, m), 7.32-7.43 (1H, m).

Example 322

[3052]1-(3,5-Difluorophenyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolinehydrochloride

[3053] The title compound was obtained from 3,5-difluorobenzonitrile bythe method similar to that in EXAMPLE 306. Yield: 42%.

[3054] Melting point: 198-199° C. (ethyl acetate-hexane-diethyl ether).

[3055]¹H NMR (CDCl₃) δ1.24 (6H, s), 1.36 (6H, s), 2.30 (2H, s), 2.69(2H, s), 3.93 (3H, s), 6.62 (1H, s), 6.71-6.90 (1H, m), 6.93-6.98 (2H,m).

Example 323

[3056]1-(2,3-Dihydro-7-methoxy-5-benzofuranyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinoline

[3057] The title compound was obtained from7-methoxy-2,3-dihydro-5-benzofurancarbonitrile by the. method similar tothat in EXAMPLE 1. Yield: 52%.

[3058] Melting point: 150-151° C. (hexane).

[3059]¹H NMR (CDCl₃) δ1.22 (6H, s), 1.34 (6H, s), 2.35 (2H, s), 2.67(2H, s), 3.23 (2H, t, J=8.8 Hz), 3.85 (3H, s), 3.92 (3H, s), 4.67 (2H,t, J=8.8 Hz), 6.60 (1H, s), 6.75 (1H, s), 6.93 (1H, s).

Example 324

[3060]N-[[4-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]methyl]methanesulfonamidehydrochloride

[3061] The title compound was obtained fromN-[(4-cyanophenyl)methyl]methanesulfonamide by the method similar tothat in EXAMPLE 306. Yield: 65%.

[3062] Melting point: 234-235° C. (ethyl acetate).

[3063]¹H NMR (DMSO-d₆) δ1.23 (6H, s), 1.45 (6H, s), 2.21 (2H, s), 2.92(3H, s), 3.17 (2H, s), 3.95 (3H, s), 4.33 (2H, d, J=3.8 Hz), 7.10 (1H,s), 7.61(4H, s), 7.84 (1H, br).

Example 325

[3064]3,4,8,9-Tetrahydro-6-methoxy-1-(6-methoxy-3-pyridinyl)-3,3,8,8-tetramethylfuro[2,3-h]isoquinolinehydrochloride p The title compound was obtained from6-methoxy-3-pyridinecarbonitrile by the method similar to that inEXAMPLE 306. Yield: 6%.

[3065] Amorphous.

[3066]¹H NMR (CDCl₃) δ1.23 (6H, s), 1.35 (6H, s), 2.33 (2H, s), 2.68(2H, s), 3.93 (3H, s), 3.98 (3H, s), 6.62 (1H,as), 6.77 (1H, dd, J=8.4,0.6 Hz), 7.63 (1H, dd, J=8.4, 2.2 Hz), 8.19 (1H, d, J=2.2 Hz).

Example 326

[3067]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-[3-(1-methylethoxy)phenyl]furo[2,3-h]isoquinolinehydrochloride

[3068] The title compound was obtained as a main product from3-(1-methylethoxy)benzonitrile by the method similar to that in EXAMPLE306. Yield: 26%.

[3069] Melting point: 191-193° C. (ethyl acetate-hexane-diethyl ether).

[3070]¹H NMR (CDr1₃) δ1.24 (6H, s), 1.30-1.33 (12H, m), 2.26 (2H, s),2.69 (2H, s), 3.92 (3H, s), 4.52-4.63 (1H, m), 6.60 (1H, s), 6.89-6.96(3H, m), 7.27 (1H, t,J=7.4 Hz).

Example 327

[3071]3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenol

[3072] The title compound was obtained as a by-product in EXAMPLE 326.Yield: 17%.

[3073] Melting point: 208-209° C. (hexane).

[3074]¹H NMR (CDCl₃) δ1.23 (6H, s), 1.31 (6H, s), 2.28 (2H, s), 2.74(2H, s), 3.93 (3H, s), 6.61-6.73 (3H, m), 6.85 (1H, t, J=2.2 Hz), 7.09(1H, t, J=7.8 Hz).

Example 328

[3075]3,4,8,9-Tetrahydro-6-methoxy-1-(6-methoxybenzothiazol-2-yl)-3,3,8,8-tetramethylfuro[2,3-h]isoquinoline

[3076] The title compound was obtained from2-cyano-6-methoxybenzothiazole by the method similar to that in EXAMPLE1.

[3077] Yield: 18%.

[3078] Melting point: 170-171° C. (ethyl acetate-hexane).

[3079]¹H NMR (CDCl₃) δ1.27 (6H, s), 1.38 (6H, s), 2.70 (2H, s), 2.79(2H, s), 3.91 (3H, s), 3.92 (3H, s), 6.61 (1H, s), 7.11 (1H, dd, J=9.0,2.5 Hz), 7.39 (1H, d, J=2.5 Hz), 7.93 (1H, d, J=9.0 Hz).

Example 329

[3080]3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)pyridine1-oxide

[3081] The title compound was obtained from 3-cyanopyridine 1-oxide bythe method similar to that in EXAMPLE 1. Yield: 27%.

[3082] Melting point: 145-146° C. (ethyl acetate-hexane-diisopropylether).

[3083]¹H NMR (CDCl₃) δ1.24 (6H, s), 1.37 (6H, s), 2.39 (2H, s), 2.70(2H, s), 3.93 (3H, s), 6.63 (1H, s), 7.27-7.32 (2H, m), 8.22-8.26 (1H,m), 8.28 (1H, s).

Example 330

[3084]1-(6-Chloro-3-pyridinyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinoline

[3085] The title compound was obtained from 6-chloronicotinonitrile bythe method similar to that in EXAMPLE 1. Yield: 11%.

[3086] Melting point: 140-141° C. (hexane).

[3087]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.36 (6H, s), 2.28 (2H, s), 2.70(2H, s), 3.93 (3H, s), 6.63 (1H, s), 7.38 (1H, d, J=7.8 Hz), 7.74 (1H,dd, J=7.8, 2.2 Hz), 8.42 (1H, d, J=2.0 Hz).

Example 331

[3088]2-[2-Oxo-5-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-1(2H)-pyridinyl]-4-pyridinecarboxamide

[3089] A solution of1-(6-chloro-3-pyridinyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinoline(1.0 g, 2.7 mmol), 4-pyridinecarboxamide 1-oxide (2.9 g, 21 mmol), 25%solution of hydrogen bromide/acetic acid (2.0 mL) and acetic acid (6.0mL) in toluene (10 mL) was heated under reflux for 30 hours. Thereaction solution was cooled to room temperature, and then the reactionmixture was poured into water. After basifying by the addition of 8 Maqueous solution of sodium hydroxide, the organic material was extractedwith ethyl acetate. The extract was washed with brine, dried over sodiumsulfate, and then the solvent was distilled off under reduced pressure.The resultant residue was purified by a column chromatography on a basicsilica gel (chloroform/methanol 100:1 followed by 20:1) to obtain thetitle compound (0.46 g, yield: 48%).

[3090] Amorphous.

[3091]¹H NMR (CDCl₃) δ1.20 (6H, s), 1.46 (6H, s), 2.65 (2H, s), 2.88(2H, s), 3.93 (3H, s), 6.03 (1H, br), 6.62 (1H, s), 6.70 (1H, d, J=9.2Hz), 7.04 (1H, br), 7.61 (1H, dd, J=9.2, 2.6 Hz), 7.79 (1H, d, J=5.0Hz), 8.08 (1H, d, J=3 2.6 Hz), 8.28 (1H, s), 8.65 (1H, d, J=5.0 Hz).

Example 332

[3092]1-(2-Pyridinyl)-5-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2(1H)-pyridinone

[3093] The title compound was obtained from pyridine 1-oxide by themethod similar to that in EXAMPLE 331. Yield: 47%.

[3094] Melting point: 203-204° C. (ethyl acetate-hexane).

[3095]¹H MMR (CDCl₃) δ1.20 (6H, s), 1.46 (6H, s), 2.65 (2H, s), 2.90(2H, s), 3.93 (3H, s), 6.62 (1H, s), 6.69 (1H, d, J=9.4 Hz), 7.33 (1H,td, J=5.8, 1.2 Hz), 7.57 (1H, dd, J=9.4, 2.6 Hz), 7.80-7.95 (2H, m),8.06 (1H, d, J=2.2 Hz), 8.55 (1H, d, J=4.2 Hz).

Example 333

[3096]1-(4-Methyl-2-quinolinyl)-5-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2(1H)-pyridinone

[3097] The title compound was obtained from 4-methylquinoline 1-oxide bythe method similar to that in EXAMPLE 331. Yield: 51%.

[3098] Melting point: 212-213° C. (ethyl acetate-hexane-diisopropylether).

[3099]¹H NMR (CDCl₃) δ1.21 (6H, s), 1.52 (6H, s), 2.65 (2H, s), 2.76(3H, s), 2.99 (2H, br s), 3.93 (3H, s), 6.62 (1H, s), 6.74 (1H, d, J=8.8Hz), 7.57-7.75 (4H, m), 8.00-8.09 (3H, m).

Example 334

[3100]1-(3-Methyl-2-quinolinyl)-5-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2(1H)-pyridinone

[3101] The title compound was obtained from 3-methylquinoline

[3102] 1-oxide by the method similar to that in EXAMPLE 331. Yield: 58%.

[3103] Melting point: 212-213° C. (ethyl acetate-hexane-diisopropylether)

[3104]¹H NMR (CDCl₃) δ1.11 (3H, s), 1.30 (3H, s), 1.66 (6H, s), 2.42(3H, s), 2.54-2.69 (2H, m), 2.73 (1H, d, J=16.2 Hz), 3.29 (1H, br d,J=16.2 Hz), 3.90 (3H, s), 6.58 (1H, s), 6.74 (1H, d, J=9.4 Hz),7.53-7.83 (5H, m), 7.99 (¹H, d, J=8.0 Hz), 8.10 (1H, s).

Example 335

[3105]1-(7-Methyl-2-quinolinyl)-5-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2(1H)-pyridinone.

[3106] The title compound was obtained from 7-methylquinoline 1-oxide bythe method similar to that in EXAMPLE 331. Yield: 6%.

[3107] Melting point: 232-233° C. (ethyl acetate-hexane).

[3108]¹H NMR (CDCl₃) δ1.23 (6H, s), 1.58 (6H, s), 2.56 (2H, s), 2.58(3H, s), 3.01 (2H, s), 3.93 (3H, s), 6.71 (1H, d, J=9.4 Hz), 6.93 (1H,s), 7.44 (1H, dd, J=8.4, 1.4 Hz), 7.72-7.88 (4H, m), 8.23 (1H, d, J=8.4Hz), 8.31 (1H, d, J=1.8 Hz).

Example 336

[3109]2-[2-Oxo-5-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-1(2H)-pyridinyl]-4-pyridinecarboxylicacid ethyl ester dihydrochloride

[3110] A free base of the title compound was obtained from4-pyridinecarboxylic acid ethyl ester 1-oxide by the method similar tothat in EXAMPLE 331. This was dissolved in ethanol, combined with 3.3 Msolution of hydrogen chloride/ethanol, and concentrated under reducedpressure to obtain the title compound. Yield: 36%.

[3111] Amorphous.

[3112]¹H NMR (CDCl₃) δ1.20 (6H, s), 1.42 (3H, t, J=7.4 Hz), 1.46 (6H,s), 2.65 (2H, s), 2.89 (2H, s), 3.93 (3H, s), 4.44 (2H, q, J=7.4 Hz),6.62 (1H, s), 6.71 (1H, d, J=9.3 Hz), 7.59 (1H, dd, J=9.3, 2.4 Hz), 7.89(1H, dd, J=4.8, 1.4 Hz), 8.04 (1H, d, J=2.4 Hz), 8.47 (1H, s), 8.67 (1H,d, J=4.8 Hz).

Example 337

[3113]5-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2(1H)-pyridinone

[3114] A solution of1-(6-chloro-3-pyridinyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin(4.0 g, 11 mmol) in 6 M hydrochloric acid (40 mL) was heated underreflux for 11.5 hours. The reaction solution was cooled to roomtemperature, basified by the addition of 8 M aqueous solution of sodiumhydroxide, and then the organic material was extracted with ethylacetate. The extract was washed with brine, dried over sodium sulfate,and then the solvent was distilled off under reduced pressure. Theresultant residue was crystallized from ethyl acetate-hexane-diisopropylether to obtain the title compound (3.6 g, yield: 94%).

[3115] Melting point: 195-196° C.

[3116]¹H NMR (CDCl₃) δ1.17 (6H, s), 1.38 (6H, s), 2.59 (2H, s), 2.61(2H, s), 3.91 (3H, s), 6.31 (1H, br), 6.52 (1H, d, J=9.3 Hz), 6.58 (1H,s), 7.41 (1H, dd, J=9.3, 2.2 Hz), 7.68 (1H, d, J=2.2 Hz).

Example 338

[3117]1-Methyl-5-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2(1H)-pyridinone

[3118] A solution of5-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2(1H)-pyridinone(1.0 g, 2.8 mmol) and sodium hydride (60% in oil, 0.35 g, 8.8 mmol) inN,N-dimethylformamide (10 mL) was stirred at room temperature. for 15minutes. Iodomethane (2.0 mL, 32 mmol) was added to the reaction mixtureat room temperature and the mixture was stirred at room temperature for9 hours. The reaction solution was poured into water, and basified bythe addition of 1 M aqueous solution of sodium hydroxide, and then theorganic material was extracted with ethyl acetate. The extract waswashed with brine, dried over sodium sulfate, and then the solvent wasdistilled off under reduced pressure. The resultant residue was purifiedby a column chromatography.on a basic silica gel(hexane/chloroform/ethyl acetate 2:1:1 followed by 1:2:2) to obtaincrude crystals. The resultant crude crystals were recrystallized fromethyl acetate-hexane-diisopropyl ether to obtain the title compound(0.52 g, yield: 50%).

[3119] Melting point: 158-159° C.

[3120]¹H NMR (CDCl₃) δ1.20 (6H, s), 1.41 (6H, s), 2.61 (2H, s), 2.65(2H, s), 3.60 (3H, s), 3.93 (3H, s), 6.56 (1H, d, J=9.4 Hz), 6.61 (1H,s), 7.33 (1H, dd, J=9.4, 2.6 Hz), 7.59 (1H, d, J=2.6 Hz).

Example 339

[3121]1-(3-Pyridinylmethyl)-5-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2(1H)-pyridinone

[3122] The title compound was obtained from 3-(chloromethyl)pyridinehydrochloride by the method similar to that in EXAMPLE 338. Yield: 38%.

[3123] Melting point: 247-248° C. (ethyl acetate-hexane).

[3124]¹H NMR (CDCl₃) δ1.19 (6H, s), 1.33 (6H, s), 2.47 (2H, s), 2.64(2H, s), 3.91 (3H, s), 5.18 (2H, s), 6.60 (1H, s), 6.65 (1H, d, J=9.4Hz), 7.27-7.32 (1H, m), 7.42 (H, dd, J=9.4, 2.6 Hz), 7.51 (1H, d, J=2.2Hz), 7.77 (1H, dd, J=7.6, 1.8 Hz), 8.57 (1H, dd, J=4.8. 1.4 Hz), 8.64(1H, d, J=2.2 Hz).

Example 340

[3125]1-(4-Pyridinylmethyl)-5-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2(1H)-pyridinone

[3126] The title compound was obtained from 4-(chloromethyl)pyridinehydrochloride by the method similar to that in EXAMPLE 338. Yield: 63%.

[3127] Melting point: 199-200° C. (ethyl acetate-diisopropyl other).

[3128]¹H NMR (CDCl₃) δ1.19 (6H, s), 1.35 (6H, s), 2.52 (2H, s), 2.64(2H, s), 3.92 (3H, s), 5.17 (2H, s), 6.61 (1H, s), 6.68 (1H, d, J=9.8Hz), 7.21 (2H, d, J=5.8 Hz), 7.45-7.48 (2H, m), 8.59 (2H, d, J=5.8 Hz).

Example 341

[3129]1-(2-Pyridinylmethyl)-5-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2(1H)-pyridinone

[3130] The title compound was obtained from 2-(chloromethyl)pyridinehydrochloride by the method similar to. that in EXAMPLE 338. Yield: 72%.

[3131] Melting point: 191-192° C. (ethyl acetate-hexane).

[3132]¹H NMR (CDCl₃) δ1.20 (6H, s), 1.35 (6H, s), 2.57 (2H, s), 2.65(2H, s), 3.92 (3H, s), 5.22 (2H, s), 6.60 (1H, s), 6.61 (1H, d, J=9.0Hz), 7.17-7.27 (1H, m), 7.42 (1H, dd, J=9.2, 2.2 Hz), 7.49 (1H, d, J=7.6Hz), 7.67 (1H, dd, J=7.6, 1.8 Hz), 7.72 (1H, d, J=2.2 Hz), 8.52 (1H, d,J=4.8 Hz).

Example 342

[3133]1-(2-Quinolinylmethyl)-5-(3,4,8,9-tatrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2(1H)-pyridinone

[3134] The title compound was obtained from 2-(chloromethyl)quinolinehydrochloride by the method similar to that in EXAMPLE 338. Yield: 54%.

[3135] Melting point: 210-211° C. (ethyl acetate-diisopropyl ether).

[3136]¹H NMR (CDCl₃) δ1.19 (6H, s, 1.23 (6H, s), 2.53 (2H, s), 2.64 (2H,s), 3.91 (3H, s), 5.45 (2H, s), 6.59 (1H, s), 6.66 (1H, d, J=9.6 Hz),7.37-7.50 (1H, m), 7.53-7.59 (2H, m), 7.65-7.73 (1H, m), 7.75 (1H, d,J=2.2 Hz), 7.81 (1H, d, J=8.0 Hz), 7.98 (1H, d, J=8.6 Hz), 8.15 (1H, d,J=8.8 Hz).

Example 343

[3137]1-(Phenylmethyl)-5-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2(1H)-pyridinone

[3138] The title compound was obtained from benzyl bromide by the methodsimilar to that in EXAMPLE 338. Yield: 38%.

[3139] Melting point: 216-217° C. (ethyl acetate-hexane-diisopropylether).

[3140]¹H NMR (CDCl₃) δ1.18 (6H, s), 1.30 (6H, s), 2.44 (2H, s), 2.63(2H, s), 3.91 (3H, s), 5.17 (2H,br s), 6.58 (1H, s), 6.66 (1H, d, J=9.8Hz), 7.32 (5H, s), 7.38-7.43 (2H, m).

Example 344

[3141]2-Oxo-5-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-1(2H)-pyridineacetamidehydrochloride

[3142] A solution of5-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2(1H)-pyridinone(1.5 g, 4.3 mmol) and sodium hydride (60% in oil, 0.19 g, 4.8 mmol) inN,N-dimethylformamide (10 mL) was stirred at room temperature for 25minutes. 2-Chloroacetamide (0.51 g, 5.5 mmol) was added to the reactionmixture at room temperature and the mixture was stirred at roomtemperature for 24 hours. The reaction solution was poured into water,basified by the addition of 1 M aqueous solution of sodium hydroxide,and then the organic material was extracted with ethyl acetate. Theextract was washed with brine, dried over sodium sulfate, and then thesolvent was distilled off under reduced pressure. The resultant residuewas purified by a column chromatography on a basic silica gel(chloroform/methanol 50:1 followed by 20:1) to obtain crude crystals.3.3 M solution of hydrogen chloride/ethanol (5.0 mL, 17 mmol) was addedto the solution of the resultant crude crystals in ethanol (20 mL) andthe mixture was stirred at room temperature for 10 minutes. The reactionsolution was concentrated under reduced pressure to obtain the titlecompound (1.3 g, yield: 59%).

[3143] Amorphous.

[3144]¹H NMR (DMSO-c) δ1.34 (6H, s), 1.40 (6H, s), 2.78 (2H, br), 3.08(2H, s), 3.93 (3H, s), 4.60 (2H, br), 6.59 (1H, d, J=9.5 Hz), 7.06 (1H,s), 7.73 (1H, dd, J=9.5, 2.4 Hz), 7.76 (1H, s), 8.27 (1H, d, J=2.4 Hz),8.33 (1H, s), 12.39 (1H, br).

Example 345

[3145]2-Oxo-5-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-1(2H)-pyridineaceticacid ethyl ester

[3146] The title compound was obtained from ethyl bromoacetate by themethod similar to that in Example 338. Yield: 17%.

[3147] Amorphous.

[3148]¹H NMR (CDCl₃) δ1.20 (6H, s), 1.30 (3H, t, J=7.4 Hz), 1.42 (6H,s), 2.65 (2H, s), 2.73 (2H, s), 3.92 (3H, s), 4.25 (2H, q, J=7.4 Hz),4.68 (2H, br), 6.60-6.65 (2H, m), 7.42-7.47 (2H, m).

Example 346

[3149]2-Oxo-N-(3-pyridinyl)-5-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-1(2H)-pyridineacetamide

[3150] A solution of2-oxo-5-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-1(2H)-pyridineaceticacid ethyl ester (1.4 g, 3.2 mmol) and 3-aminopyridine (0.58 g, 6.2mmol) in decalin (10 mL) was stirred at 200° C. for 17 hours under argonatmosphere. The reaction solution was combined with 2 M hydrochloricacid, and washed with chloroform. The aqueous solution was basified with8 M aqueous solution of sodium hydroxide, and then the organic materialwas extracted with ethyl acetate. The extract was washed with brine,dried over sodium sulfate, and then the solvent was distilled off underreduced pressure. The resultant residue was purified by a columnchromatography on a basic silica gel (ethyl acetate/methanol 50:1followed by 10:1) to obtain crude crystals. The resultant crude crystalswere recrystallized from ethyl acetate-diisopropyl ether to obtain thetitle compound (0.20 g, yield: 13%).

[3151] Melting point: 276-277° C.

[3152]¹H NMR (CDCl₃) δ1.21 (6H, s), 1.40 (6H, s), 2.66 (4H, s), 3.93(3H, s), 4.78 (2H, br s), 6.62 (1H, s), 6.71 (1H, d, J=9.3 Hz),7.18-7.27 (1H, m), 7.56 (1H, dd, J=9.3, 2.6 Hz), 7.69 (1H, d, J=2.2 Hz),8.04-8.08 (1H, m), 8.33 (1H, dd, J=4.6, 1.4 Hz), 8.63 (1H, d, J=2.6 Hz),9.65 (1H, s).

Example 347

[3153]N-(2-Hydroxyethyl)-2-oxo-5-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tatramethylfuro[2,3-h]:isoquinolin-1-yl)-1(2H)-pyridineacetamide

[3154] The title compound was obtained from 2-aminoethanol by the methodsimilar to that in EXAMPLE 346. Yield: 59%.

[3155] Melting point: 133-134° C. (ethyl acetate-diisopropyl ether).

[3156]¹H NMR (CDCl₃) δ1.20 (6H, s), 1.42 (6H, s), 2.65 (2H, s), 2.68(2H, s), 3.41 (2H, m), 3.69 (2H, t, J=4.8 Hz), 3.92 (3H, s), 4.64 (2H,s), 6.61 (1H, s), 6.62 (1H, d, J=7.6 Hz) 7.37-7.48 (2H, m), 7.63 (1H, d,J=2.2 Hz).

Example 348

[3157] 2-Oxo-5-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-1 (2H)-pyridineacetic acid 1,1-dimethylethylester

[3158] The title compound was obtained from tert-butyl bromoacetate bythe method similar to that in EXAMPLE 338.

[3159] Yield: 51%.

[3160] Amorphous.

[3161]¹H NMR (CDCl₃) δ1.20 (6H, s), 1.42 (15H, s), 2.65 (2H, s), 2.72(2H, s), 3.92 (3H, s), 4.65 (2H, br), 6.61-6.65 (2H, m), 7.40-7.48 (2H,m).

EXAMPLE 349

[3162]2-Oxo-5-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-1(2H)-pyridineacetic acid hydrochloride

[3163] A solution of2-oxo-5-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-1(2H)-pyridineaceticacid 1,1-dimethylethyl ester (2.7 g, 5.8 mmol) in 6 M hydrochloric acid(30 mL) was heated under reflux for 1 hour. After cooling to roomtemperature, the reaction mixture was concentrated under reduced.pressure. The resultant residue was crystallized fromchloroform-diisopropyl ether to obtain the title compound (2.5 g, yield:97%).

[3164] Melting point: 231-233° C. (decomposition).

[3165]¹H NMR (DMSO-d₆) δ1.34 (6H, s), 1.39 (6H, s), 2.80 (2H, br), 3.08(2H, s), 3.94 (3H, s), 4.71 (2H, s), 6.63 (1H, d, J=9.6 Hz), 7.07 (1H,s), 7.76 (1H, dd, J=9.6, 3.0 Hz), 8.33 (1H, d, J=3.0 Hz), 12.40 (1H,br).

Example 350

[3166]4-[[2-Oxo-5-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-1(2H)-pyridinyl]methyl]benzoicacid methyl ester

[3167] The title compound was obtained from methyl4-(bromomethyl)benzoate by the method similar to that in EXAMPLE 338.Yield: 62%.

[3168] Amorphous.

[3169]¹H NMR (CDCl₃) δ1.18 (6H, s), 1.32 (6H, s), 2.47 (2H, s), 2.63(2H, s), 3.91 (6H, s), 5.22 (2H, br s), 6.60 (1H, s), 6.67 (1H, d, J=9.8Hz), 7.37-7.46 (4H, m), 8.01 (2H, d, J=8.4 Hz).

Example 351

[3170]N-(2-Hydroxyethyl)-4-[[2-oxo-5-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro,[2,3-h]isoquinolin-1-yl)-1(2H)-pyridinyl]methyl]benzamidehydrochloride

[3171] A solution of 4-[[2-oxo-S-(3,4,8,9-tetrahydro-6-methoxy-3,3,88-tetramethylfuro[2,3-h]isoquinolin-1-yl)-1(2H)-pyridinyl]methyl]benzoicacid methyl ester (1.0 g, 2.0 mmol) and 2-aminoethanol (2.0 mL, 33 mmol)in xylene (10 mL) was heated under reflux for 4 hours. The reactionsolution was cooled to room temperature, and the solvent was distilledoff under reduced pressure. The residue was combined with water, and themixture was made alkaline with 1 M aqueous solution of sodium hydroxide,and then the organic material was extracted with ethyl acetate. Theextract was washed with brine and dried over sodium sulfate, and thenthe solvent was distilled off under reduced pressure. The resultantresidue was purified by a column chromatography on a basic silica gel(ethyl acetate/methanol 50:1 followed by 20:1) to obtain crude crystals.3.3 M hydrogen chloride/ethanol solution (3.0 mL, 10 mmol) was added toa solution of the resultant crude crystals in ethanol (20 mL) and themixture was stirred at room temperature for 10 minutes. The reactionsolution was concentrated under reduced pressure, and the resultantresidue was crystallized from chloroform-diisopropyl ether to obtain thetitle compound (1.1 g, Yield: 96%).

[3172] Melting point: 175-176° C.

[3173]¹H NMR (DMSO-d₆) δ1.28 (6H, s), 1.42 (6H, s), 2.66 (2H, s), 3.09(2H, s), 3.30-3.40 (2H, m), 3.50 (2H, t, J=5.6 Hz), 3.93 (3H, s), 5.24(2H, br), 6.62 (1H,d, J=9.6 Hz), 7.07 (1H, s), 7.45 (2H, d, J=8.0 Hz),7.67 (1H, dd, J=9.4, 2.2 Hz), 7.88 (2H, d, J=8.0 Hz), 8.51-8.57 (2H, m).

Example 352

[3174]4-[[2-Oxo-5-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-1(2H)-pyridinyl]methyl]benzoicacid hydrochloride

[3175] The title compound was obtained from4-[[2-oxo-5-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-1(2H)-pyridinyl]methyl]benzoicacid methyl ester by the method similar to that in EXAMPLE 349. Yield:62%.

[3176] Amorphous. 1H NMR (DMSO-d₆) δ1.27 (6H, s), 1.42 (6H, s), 2.65(2H, s), 3.09 (2H, s), 3.93 (3H, s), 5.30 (2H, br), 6.64 (1H, d, J=9.6Hz), 7.08 (1H, s), 7.49 (2H, d, J=8.4 Hz), 7.70 (1H, dd, J=9.6, 2.2 Hz),7.93 (2H, d, J=8.4 Hz), 8.58 (1H, d, J=2.2 Hz), 12.62 (1H, br).

Example 353

[3177]4-[[2-Oxo-5-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-1(2H)-pyridinyl]methyl]benzamide

[3178] N,N-Dimethylformamide (0.1 mL) was added to a solution of4-[[2-oxo-5-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-1(2H)-pyridinyl]methyl]benzoicacid hydrochloride (1.6 g, 3.1 mmol) and oxalyl chloride (0.75 mL, 8.6mmol) in tetrahydrofuran (50 mL) at room temperature and the reactionmixture was stirred at room temperature for 1 hour. The reactionsolution was concentrated under reduced pressure. 6.3 M ammonia/ethanolsolution (30 mL) was added to a solution of the resultant residue intetrahydrofuran (50 mL) at room temperature, and the reaction mixturewas stirred at room temperature for 1 hour. The reaction solution wasconcentrated under reduced pressure, and the residue was combined withwater, and the organic material was extracted with chloroform. Theextract was washed with brine and dried over sodium sulfate, and thenthe solvent was distilled off under reduced pressure. The resultant.residue was purified by a column chromatography on a basic silica gel(chloroform/methanol 50:1 followed by 20:1) to obtain crude crystals.The resultant crude crystals were recrystallized from ethyl acetate toobtain the title compound (0.44 g, Yield: 31%).

[3179] Melting point: 262-266° C.

[3180]¹H NMR (CDCl₃) δ1.18 (6H, s), 1.33 (6H, s), 2.49 (2H, s), 2.63(2H, s), 3.91 (3H, s), 5.21 (2H, s), 5.64 (1H, br), 6.08 (1H, br), 6.60(1H, s), 6.66 (1H, d, J=9.0 Hz), 7.39-7.47 (4H, m), 7.79 (2H, d, J=8.0Hz).

Example 354

[3181]N-Methyl-4-[[2-oxo-5-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-1(2H)-pyridinyl]methyl]benzamide

[3182] The title compound was obtained from a 40% methylamine/methanolsolution by the method similar to that in. EXAMPLE 353. Yield: 41%.

[3183] Amorphous.

[3184]¹H NMR (CDCl₃) δ1.18 (6H, s), 1.33 (6H, s), 2.49 (2H, s), 2.63(2H, s), 3.00 (3H, d, J=5.2 Hz), 3.91 (3H, s), 5.20 (2H, br), 6.18 (1H,br), 6.59 (1H, s), 6.65 (1H, d, J=10 Hz), 7.36-7.46 (4H, m), 7.73 (2H,d, J=8.0 Hz).

Example 355

[3185]4-[[2-Oxo-5-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2.3-h]isoquinolin-1-yl)-1(2H)-pyridinyl]methyl]-N-propylbenzamide

[3186] The title compound was obtained from propylamine by the methodsimilar to EXAMPLE 353. Yield: 57%.

[3187] Melting point: 193-195° C. (ethyl acetate-hexane-diisopropylether).

[3188]¹H NMR (CDCl₃) δ0.97 (3H, t, J=7.2 Hz), 1.18 (6H, s), 1.33 (6H,s), 1.55-1.65 (2H, m), 2.48 (2H, s), 2.63 (2H, s), 3.41 (2H, q, J=7.2Hz), 3.91 (3H, s), 5.20 (2H, s), 6.12 (1H, br), 6.59 (1H, s), 6.65 (1H,d, J=9.0 Hz), 7.37-7.45 (4H, m), 7.73 (2H, d, J=8.0 Hz).

Example 356

[3189]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-[4-(methylthio)phenyl]furo[2,3-h]isoquinolinehydrochloride

[3190] A solution of 4-(methylthio)benzonitrile (0.776 g, 5.20 mmol) intoluene (5 mL) and acetic acid (5 mi) was treated dropwise with conc.sulfuric acid (0.5 mL) with cooling in ice. The ice bath was removed,and a solution of2,3-dihydro-7-methoxy-2,2-dimethyl-5-(2-methyl-1-propenyl)benzofuran(0.929 g, 4.00 mmol) in toluene (5 mL) was added and the mixture wasstirred at 80° C. for 1 hour. The reaction mixture was combined withice, and the aqueous layer was neutralized with conc. aqueous ammoniaand extracted twice with ethyl acetate. The combined organic layer waswashed with water and brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was subjected to acolumn chromatography on a silica gel (hexane/ethyl acetate 2:1) toobtain a free base of the title compound. This was combined with 2.8 Mhydrogen chloride/ethanol solution (7.4 mL) and the mixture wasconcentrated under reduced pressure. The residue was crystallized fromdiethyl ether, and recrystallized from ethyl acetate to obtain the titlecompound (0.72 g, Yield: 43%).

[3191] Melting point: 137-140° C.

[3192]¹H NMR (CDCl₃) δ1.37 (6H, s), 1.67 (6H, s), 2.39 (2H, s), 2.55(3H, s), 3.00 (2H, s), 4.02 (3H, s), 6.74 (1H, s), 7.36 (2H, d, J=8.2Hz), 7.68 (2H, d, J=8.2 Hz).

Example 357

[3193]1-(2,3-Dihydro-5-benzofuranyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolinehydrochloride

[3194] The title compound was obtained from2,3-dihydro-5-benzofurancarbonitrile by the method similar to that inEXAMPLE 356. Yield: 51%.

[3195] Melting point: 144-148° C. (ethyl acetate).

[3196]¹H NMR (CDCl₃) δ1.39 (6H, s), 1.65 (6H, s), 2.45 (2H, s), 2.98(2H, s), 3.36 (2H, t, J=8.8 Hz), 4.01 (3H, s), 4.72 (2H, t, J=8.8 Hz),6.73 (1H, s), 6.86 (1H, d, J=8.4 Hz), 7.32 (1H, dd, J=8.4, 1.8 Hz), 7.93(1H, d, J=1.8 Hz).

Example 358

[3197]1-(1,3-Benzodioxol-5-yl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolinehydrochloride

[3198] The title compound was obtained from1,3-benzodioxol-5-carbonitrile by the method similar to that in EXAMPLE356.

[3199] Yield: 44%.

[3200] Melting point: 156-160° C. (ethyl acetate).

[3201]¹H NMR (CDCl₃) δ1.39 (6H, s), 1.65 (6H, s), 2.45 (2H, s), 2.99(2H, s), 4.01 (3H, s), 6.11 (2H, s), 6.73 (1H, s), 6.97 (1H, d, J=8.0Hz), 7.17 (1H, br s), 7.27-7.29 (1H, m).

Example 359

[3202]N,N-Dimethyl-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenaminehydrochloride

[3203] The title compound was obtained from4-(dimethylamino)benzonitrile by the method similar to that in Example356. Yield: 24%.

[3204] Melting point: 165-168° C. (ethyl acetate-ethanol).

[3205]¹H NMR (CDCl₃) δ1.40 (6H, s), 1.62 (6H, s), 2.58 (2H, s), 2.94(2H, s), 3.10 (6H, s), 4.01 (3H, s), 6.73 (1H, s), 6.75 (2H, d, J=9.0Hz), 7.77 (2H, d, J=9.0 Hz).

Example 360

[3206]1-[4-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]ethanonehydrochloride

[3207] The title compound was obtained from 4-acetylbenzonitrile by themethod similar to that in EXAMPLE 356.

[3208] Yield: 29%.

[3209] Melting point: 167-170° C. (ethyl acetate-ethanol).

[3210]¹H NMR (CDCl₃) δ1.34 (6H, s), 1.71 (6H, s), 2.21 (2H, s), 2.69(3H, s), 3.06 (2H, s), 4.03 (3H, s), 6.77 (1H, s), 7.80 (2H, d, J=8.2Hz), 8.14 (2H, d, J=8.2 Hz).

Example 361

[3211]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-(2-thienyl)furo[2,3-h]isoquinolinehydrochloride

[3212] Title compound was obtained from 2-thiophenecarbonitrile by themethod similar to that in EXAMPLE 356. Yield: 30%.

[3213] Melting point: 154-156° C. (ethyl acetate-ethanol).

[3214] 1H NMR (CDCl₃) δ1.41 (6H, s), 1.66 (6H, s), 2.59 (2H, s), 3.00(2H, s), 4.02 (3H, s), 6.75 (1H, s), 7.29 (1H, br s), 7.82 (1H, d, J=4.6Hz), 8.05 (1H, br s).

Example 362

[3215]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-[4-(trifluoromethyl)phenyl]furo[2,3-h]isoquinolinehydrochloride

[3216] The title compound was obtained from4-(trifluoromethyl)benzonitrile by the method similar to that in EXAMPLE356. Yield: 53%.

[3217] Melting point: 149-151° C. (ethyl acetate).

[3218]¹H NMR (CDCl₃) δ1.35 (6H, s), 1.71 (6H, s), 2.19 (2H, s), 3.05(2H, s), 4.03 (3H, s), 6.77 (1H, s), 7.84 (4H, s).

Example 363

[3219]1-(2,3-Dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolinehydrochloride

[3220] The title compound was obtained from2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofurancarbonitrile by themethod similar to that in EXAMPLE 356. Yield: 38%.

[3221] Melting point: 141-143° C. (diethyl ether-ethyl acetate).

[3222]¹H NMR (CDCl₃) δ1.40 (6H, s), 1.56 (6H, s), 1.66 (6H, s), 2.50(2H, s), 2.97 (2H, s), 3.08 (2H, s), 4.02 (3H, s), 4.06 (3H, s), 6.74(1H, s), 7.12 (1H, br s), 7.46 (1H, br s).

Example 364

[3223]Bis[3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-[4-(phenylthio)phenyl]furo[2,3-h]isoquinoline]trihydrochloride

[3224] The title compound was obtained from 4-(phenylthio)benzonitrileby the method similar to that in EXAMPLE 356. Yield: 48%.

[3225] Melting point: 130-132° C. (diethyl ether-ethyl acetate).

[3226]¹H NMR (CDCl₃) δ1.37 (6H, s), 1.67 (6H, s), 2.35 (2H, s), 3.00(2H, s), 4.01 (3H, s), 6.74 (1H, s), 7.27-7.63 (9H, m).

Example 365

[3227]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-[4-(1-methylethyl)phenyl]furo[2,3-h]isoquinolinehydrochloride

[3228] The title compound was obtained from4-(1-methylethyl)benzonitrile by the method similar to that in EXAMPLE356. Yield: 37%.

[3229] Melting point: 169-171° C. (ethyl acetate).

[3230]¹H NMR (CDCl₃) δ1.31 (6H, d, J=6.8 Hz), 1.35 (6H, s), 1.69 (6H,s), 2.29 (2H, s), 2.95-3.08 (1H, m), 3.01 (2H, s), 4.02 (3H, s), 6.75(1H, s), 7.42 (2H, d, J=8.4 Hz), 7.69 (2H, d, J=8.4 Hz).

Example 366

[3231]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-(5-methyl-2-thienyl)furo[2,3-h]isoquinolinehydrochloride

[3232] The title compound was obtained from5-methyl-2-thiophenecarbonitrile by the method similar to that inEXAMPLE 356. Yield: 12%.

[3233] Melting point: 177-179° C. (ethyl acetate).

[3234]¹H NMR (CDCl₃) δ1.39 (6H, s), 1.69 (6H, s), 2.30 (3H, s), 2.32(2H, s), 3.02 (2H, s), 4.02 (3H, s), 6.73 (1H, s), 7.01 (1H, d, J=4.8Hz), 7.60 (1H, d, J=4.8 Hz).

Example 367

[3235]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-[4-(trifluoromethoxy)phenyl]furo[2,3-h]isoquinolinehydrochloride

[3236] The title compound was obtainedfrom-4-(trifluoromethoxy)benzonitrile by the method similar to that inEXAMPLE 356. Yield: 27%.

[3237] Melting point: 163-166° C. (ethyl acetate).

[3238]¹H NMR (CDCl₃) δ1.36 (6H, s), 1.70 (6H, s), 2.25 (2H, s), 3.04(2H, s), 4.03 (3H, s), 6.76 (1H, s), 7.41 (2H, d, J=8.4 Hz). 7.81 (2H,d, J=8.4 Hz).

Example 368

[3239]2-Methoxy-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenol

[3240] A solution of 4-hydroxy-3-methoxybenzonitrile (0.895 g, 6.00mmol).in toluene (5 mL) and acetic acid (5 mL) was treated dropwise withconc. sulfuric acid (0.6 mL) with cooling in ice. The ice bath wasremoved, and a solution of2,3-dihydro-7-methoxy-2,2-dimethyl-5-(2-methyl-1-propenyl)benzofuran(1.16 g, 5.00 mmol) in toluene (5 mL) was added and stirred at 80° C.for 1 hour. The reaction mixture was combined with ice, and the aqueouslayer was neutralized with conc. aqueous ammonia, and extracted twicewith ethyl acetate. The combined organic layer was washed with water andbrine, dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was subjected to a column chromatographyon a silica gel (hexane/ethyl acetate 2:1 followed by ethyl acetate) andrecrystallized from ethyl acetate-hexane to obtain the title compound(0.92 g, Yield: 48%).

[3241] Melting point: 143-145° C.

[3242]¹H NMR (CDCl₃) δ1.24 (6H, s), 1.33 (6H, s), 2.32 (2H, s), 2.55(1H, br s), 2.68 (2H, s), 3.89 (3H, s), 3.92 (3H, s), 6.61 (1H, s),6.86-6.92 (3H, m).

Example 369

[3243]1-(3,5-Dichloro-4-pyridinyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinoline

[3244] The title compound was obtained from3,5-dichloro-4-pyridinecarbonitrile by the method similar to that inEXAMPLE 368. Yield: 23%.

[3245] Melting point: 147-148° C. (hexane).

[3246]¹H NMR (CDCl₃) δ1.34 (6H, s), 1.35 (6H, s), 2.19 (2H, s), 2.78(2H, s), 3.92 (3H, s), 6.63 (1H, s), 8.56 (2H, s).

Example 370

[3247]1-(2-Furanyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinoline

[3248] The title compound was obtained from 2-furonitrile by the methodsimilar to that in EXAMPLE 368. Yield: 25%.

[3249] Melting point: 125-127° C. (hexane).

[3250]¹H NMR (CDCl₃) δ1.23 (6H, s), 1.41 (6H, s), 2.51 (2H, s), 2.66(2H, s), 3.92 (3H, s), 6.49 (1H, dd, J=3.4, 1.8 Hz), 6.58 (1H, s), 6.66(1H, d, J=3.4 Hz), 7.48 (1H, d, J=1.8 Hz).

Example 371

[3251]2-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenol

[3252] The title compound was obtained from 2-cyanophenyl acetate by themethod similar to that in EXAMPLE 368. Yield: 19%.

[3253] Melting point: 186-189° C. (ethyl acetate-hexane).

[3254]¹H NMR (CDCl₃) δ1.22 (6H, s), 1.42 (6H, s), 2.64 (2H, s), 2.74(2H, s), 3.94 (3H, s), 6.64 (1H, s), 6.75-6.84 (1H, m), 6.98-7.03 (1H,m), 7.24-7.32 (2H, m).

Example 372

[3255]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-(3-thienyl)furo[2,3-h]isoquinolin

[3256] The title compound was obtained from 3-thiophenecarbonitrile bythe method similar to that In EXAMPLE 368. Yield: 45%.

[3257] Melting point: 119-122° C. (hexane).

[3258]¹H NMR (CDCl₃) δ1.23 (6H, s), 1.35 (6H, s), 2.36 (2H, s), 2.67(2H, s), 3.92 (3H, s), 6.60 (1H, s), 7.11 (1H, dd, J=5.0, 1.2 Hz),7.30-7.39 (2H, m).

Example 373

[3259]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-(3-methyl-2-thienyl)furo[2,3-h]isoquinoline

[3260] The title compound was obtained from3-methyl-2-thiophenecarbonitrile by the method similar to that inEXAMPLE 368. Yield: 23%.

[3261] Melting point: 195-197° C. (hexane-ethyl acetate).

[3262]¹H NMR (CDCl₃) δ1.19 (6H, s), 1.40 (6H, s), 2.50 (3H, d, J=0.8Hz), 2.63 (2H, s), 2.67 (2H, s), 3.92 (3H, s), 6.59 (1H, s), 6.67-6.69(1H, m), 6.84 (1H, d, J=3.6 Hz).

Example 374

[3263]1-(2-Chloro-3-pyridinyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinoline

[3264] The title compound was obtained from2-chloro-3-pyridinecarbonitrile by the method similar to that in EXAMPLE368. Yield: 29%.

[3265] Melting point: 159-160° C. (ethyl acetate-hexane).

[3266]¹H NMR (CDCl₃) δ1.21 (3H, s), 1.30 (3H, s), 1.36 (3H, s), 1.39(3H, s), 2.03 (1H, d, J=15.8 Hz), 2.25 (1H, d, J=15.8 Hz), 2.70 (1H, d,J=15.8 Hz), 2.81 (1H, d, J=15.8 Hz), 3.92 (3H, s), 6.62 (1H, s), 7.34(1H, dd, J=7.2, 4.8 Hz), 7.69 (1H, dd, J=7.2, 1.8 Hz), 8.46 (1H, dd,J=4.8, 1.8 Hz).

Example 375

[3267]1-(2,6-Dichloro-4-methyl-3-pyridinyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinoline

[3268] The title compound was obtained from2,6-dichloro-4-methyl-3-pyridinecarbonitrile by the method similar tothat in EXAMPLE 368. Yield: 25%.

[3269] Melting point: 97-101° C. (ethyl acetate-hexane).

[3270]¹H NMR (CDCl₃) δ1.32 (3H, s), 1.33 (3H, s), 1.34 (3H, s), 1.37(3H, s), 2.02 (1H, d, J=15.8 Hz), 2.19 (3H, s), 2.32 (1H, d, J=15.8 Hz),2.74 (1H, d, J=15.8 Hz), 2.79 (1H, d, J=15.8 Hz), 3.92 (3H, s), 6.62(1H, s), 7.20 (1H, s).

Example 376

[3271]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-pyrazinylfuro[2,3-h]isoquinolin

[3272] The title compound was obtained from pyrazinecarbonitrile by themethod similar to that in EXAMPLE 368. Yield: 6%.

[3273] Melting point: 154-155° C. (ethyl acetate-hexane).

[3274]¹H NMR (CDCl₃) δ1.30 (6H, s), 1.34 (6H, s), 2.17 (2H, s), 2.74(2H, s), 3.92 (3H, s), 6.62 (1H, s), 8.57 (1H, dd, J=2.6, 1.6 Hz), 8.64(1H, d, J=2.6 Hz), 8.87 (1H, d, J=1.6 Hz).

Example 377

[3275]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-(4-nitrophenyl)furo[2,3-h]isoquinoline

[3276] The title compound was obtained from 4-nitrobenzonitrile by themethod similar to that in EXAMPLE 368. Yield: 42%.

[3277] Melting point: 152-153° C. (ethyl acetate-hexane).

[3278]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.33 (6H, s), 2.19 (2H, s), 2.71(2H, s), 3.93 (3H, s), 6.64 (1H, s), 7.60 (2H, ddd, J=8.6, 2.2, 1.8 Hz),8.27 (2H, ddd, J=8.6, 2.2, 1.8 Hz).

Example 378

[3279]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-[4-(methylsulfinyl)phenyl]furo[2,3-h]isoquinoline

[3280] The title compound was obtained from4-(methylsulfinyl)benzonitrile by the method similar to that in. EXAMPLE368. Yield: 26%.

[3281] Melting point: 120-121° C. (ethyl acetate-hexane).

[3282]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.32 (6H, s), 2.19 (2H, s), 2.70(2H, s), 2.72 (3H, s), 3.93 (3H, s), 6.63 (1H, s), 7.58 (2H, d, J=8.4Hz), 7.70 (2H, d, J=8.4 Hz).

Example 379

[3283]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-[4-(methylsulfonyl)phenyl]furo[2,3-h]isoquinoline.

[3284] The title compound was obtained from4-(methylsulfonyl)benzonitrile by the method similar to that in EXAMPLE368. Yield: 52%.

[3285] Melting point: 189-190° C. (ethyl acetate-hexane).

[3286]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.33 (6H, s), 2.18 (2H, s), 2.71(2H, s), 3.04 (3H, s), 3.93 (3H, s), 6.63 (1H, s), 7.63 (2H, d, J=8.4Hz), 7.99 (2H, d, J=8.4 Hz).

Example 380

[3287]1-(3-Furanyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2.3-h]isoquinoline

[3288] The title compound was-obtained from 3-furonitrile by the methodsimilar to that in EXAMPLE 368. Yield: 31%.

[3289] Melting point: 130-131° C. (ethyl acetate-hexane).

[3290]¹H NMR (CDCl₃) δ1.21 (6H, s), 1.40 (6H, s), 2.65 (4H, s), 3.92(3H, s), 6.46 (1H, dd, J=1.8, 0.8 Hz), 6.59 (1H, s), 7.44 (1H, dd,J=1.8, 1.4 Hz), 7.59 (1H, dd, J=1.4, 0.8 Hz).

Example 381

[3291]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-(3,4,5-trimethoxyphenyl)furo[2,3-h]isoquinoline

[3292] The title compound was obtained from 3,4,5-trimethoxybenzonitrileby the method similar to that in EXAMPLE 368. Yield: 45%.

[3293] Melting point: 186-188° C. (ethyl acetate-hexane).

[3294]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.34 (6H, s), 2.34 (2H, s), 2.69(2H, s), 3.84 (3H, s), 3.86 (6H, s), 3.93 (3H, s), 6.61-6.62 (3H, m).

Example 382

[3295]1-[2,2′-Bipyridin]-6-yl-5-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2(1H)-pyridinone

[3296] A solution of1-[2,2′-bipyridin]-6-yl-1,6-dihydro-6-oxo-3-pyridinecarbonitrile (2.06g, 7.51 mmol) in toluene (10 mL) was treated dropwise with conc.sulfuric acid (10 mL) with cooling in ice. A solution of2,3-dihydro-7-methoxy-2,2-dimethyl-5-(2-methyl-1-propenyl)benzofuran(1.45 g, 6.26 mmol) in toluene (10 mL) was added dropwise and themixture was stirred at 0° C. for 10 minutes. The reaction mixture wascombined with ice, and the aqueous layer was neutralized with conc.aqueous ammonia and extracted twice with ethyl acetate. The combinedorganic layer was washed with water and brine, dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas subjected to a column chromatography on a silica gel (1%methanol/ethyl acetate followed by 5%), recrystallized from ethylacetate-hexane to obtain the title compound (0.43 g, Yield: 17%).

[3297] Melting point: 231-234° C.

[3298]¹H NMR (CDCl₃) δ1.22 (6H, s), 1.42 (6H, s), 2.66 (2H, s), 2.89(2H, s), 3.94 (3H, s), 6.62 (1H, s), 6.76 (1H, dd, J=9.2, 0.6 Hz), 7.32(1H, ddd, J=7.2, 4.8, 1.0 Hz), 7.62 (1H, dd, J=9.2, 2.6 Hz), 7.80 (1H,ddd, J=8.0, 7.2, 1.0 Hz), 7.91-8.02 (2H, m), 8.09 (1H, dd, J=2.6, 0.6Hz), 8.28 (1H, dt, J=8.0, 1.0 Hz), 8.44 (1H, dd, J=6.6, 2.2 Hz), 8.68(1H, ddd, J=4.8, 1.8, 1.0 Hz).

Example 383

[3299]1-(8-Methyl-2-quinolinyl)-5-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2(1H)-pyridinone

[3300] The title compound was obtained from1,6-dihydro-1-(8-methyl-2-quinolinyl)-6-oxo-3-pyridinecarbonitrile bythe method similar to that in EXAMPLE 382. Yield: 29%.

[3301] Melting point: 182-183° C. (ethyl acetate-hexane).

[3302]¹H NMR (CDCl₃) δ1.22 (6H, s), 1.45 (6H, s), 2.66 (2H, s), 2.74(3H, s), 2.88 (2H, s), 3.93 (3H, s), 6.62 (¹H, s), 6.74 (1H, dd, J=9.2,0.8 Hz), 7.47 (1H, dd, J=7.6, 7.0 Hz), 7.56-7.62 (2H, m), 7.71 (1H, d,J=7.6 Hz), 7.92 (1H, d, J=8.8 Hz), 8.14 (1H, dd, J=2.6, 0.8 Hz), 8.23(1H, d, J=8.8 Hz).

Example 384

[3303]1-(4-Methyl-2-pyridinyl)-5-(3.4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2(1H)-pyridinone

[3304] A solution of1,6-dihydro-1-(4-methyl-2-pyridinyl)-6-oxo-3-pyridinecarbonitrile (3.22g, 15.2 mmol) in toluene (10 mL) was treated dropwise with conc.sulfuric acid (10 mL) with cooling in ice. A solution of2,3-dihydro-7-methoxy-2,2-dimethyl-5-(2-methyl-1-propenyl)benzofuran(2.72 g, 11.7 mmol) in toluene (10 mL) was added dropwise, and themixture was stirred at room temperature for 30 minutes. The reactionmixture was combined with ice, and the aqueous layer was neutralizedwith conc. aqueous ammonia, and extracted twice with ethyl acetate. Thecombined organic layer was washed with water and brine, dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresidue was subjected to a column chromatography on a silica gel (1%methanol/ethyl acetate followed by 5%) and further to a columnchromatography on a basic silica gel (hexane/ethyl acetate 1:1),recrystallized from ethyl acetate-hexane to obtain the title compound(1.00 g, Yield; 19%).

[3305] Melting point: 161-162° C.

[3306]¹H NMR (CDCl₃) δ1.19 (6H, s), 1.45 (6H, s), 2.44 (3H, s), 2.64(2H, s), 2.89 (2H, s), 3.92 (3H, s), 6.60 (1H, s), 6.68 (1H, d, J=9.6Hz), 7.13 (1H, ddd, J=5.2, 1.6, 0.8 Hz), 7.55 (1H, dd, J=9.6, 2.6 Hz),7.70 (1H, d, J=1.6 Hz), 8.00 (1H, d, J=2.6 Hz), 8.38 (1H, d, J=5.2 Hz).

Example 385

[3307]4-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)pyridine1-oxide

[3308] A solution of 4-cyanopyridine 1-oxide (1.26 g, 10.0 mmol) intoluene (5 mL) was treated dropwise with conc. sulfuric acid (5 mL) withcooling in ice. A solution of2,3-dihydro-7-methoxy-2,2-dimethyl-5-(2-methyl-1-propenyl)benzofuran(1.63 g, 7.00 mmol) in toluene (5 mL) was added dropwise, and themixture was stirred at 0° C. for 30 minutes and then at 80° C. for 30minutes. The reaction mixture was combined with ice, and the aqueouslayer was neutralized with conc. aqueous ammonia, and extracted twicewith ethyl acetate. The combined organic layer was washed with water andbrine, dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was subjected to a column chromatographyon a basic silica gel (ethyl acetate) and recrystallized from ethylacetate-hexane to obtain the title compound (1.33 g, Yield: 54%).

[3309] Melting point: 197-199° C.

[3310]¹H NMR (CDCl₃) δ1.23 (6H, s), 1.39 (6H, s), 2.41 (2H, s), 2.68(2H, s), 3.94 (3H, s), 6.64 (1H, s), 7.38 (2H, d, J=7.0 Hz), 8.25 (2H,d, J=7.0 Hz).

Example 386

[3311]4-Methyl-1-[4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-pyridinyl]-2(1H)-quinolinone

[3312] 25% hydrogen bromide/acetic acid solution (4 mL) was added to asolution of4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)pyridine1-oxide (3.52 g, 10.0 mmol) and 2-chloro-4-methylquinoline (3.55 g, 20.0mmol) in xylene (30 mL) and acetic acid (6 mL) and the mixture washeated under reflux for 4 hours. The reaction mixture was combinedwith.ice water, and the aqueous layer was neutralized with conc. aqueousammonia, and extracted twice with ethyl acetate. The combined organiclayer was washed with water. and brine, dried over sodium sulfate,filtered and concentrated under reduced pressure. The residue wassubjected to a column chromatography-on a basic silica gel (hexane/ethylacetate 2:1) and recrystallized from ethyl acetate to-obtain the titlecompound (2.46 g, Yield: 50%).

[3313] Melting point: 218-219° C.

[3314]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.40 (6H, s), 2.51 (3H, d, J=1.0Hz), 2.57 (2H, br s), 2.68 (2H, s), 3.91 (3H, s), 6.59 (1H, s), 6.61(1H, d, J=1.0 Hz), 6.64 (1H, dd, J=8.4, 1.2 Hz), 7.17-7.25 (1H, m),7.29-7.38 (2H, m), 7.61 (1H, dd, J=5.2, 1.6 Hz), 7.70 (1H, dd, J=8.0,1.4 Hz), 8.82 (1H,dd, J=5.2, 0.8 Hz).

Example 387

[3315]1-[4-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-pyridinyl]-2(1H)-pyridinone

[3316] 25% hydrogen bromide/acetic acid solution (6 mL) was added to asolution of4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)pyridine1-oxide (5.00 g, 14.2 mmol) and 2-chloropyridine (16.1 g, 142 mmol) inxylene (45 mL) and acetic.acid (9 mL) and the mixture was heated underreflux for 8 hours. The reaction mixture was combined with ice water,and the aqueous layer was neutralized with conc. aqueous ammonia, andextracted twice with ethyl acetate. The combined organic layer waswashed with water and brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was subjected to acolumn chromatography on a silica gel (ethyl acetate) followed by a.column chromatography on a basic silica gel (hexane/ethyl acetate 1:1),and recrystallized from ethyl acetate to obtain the title compound (1.55g, Yield: 25%).

[3317] Melting point: 223-224° C.

[3318]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.38 (6H, s), 2.54 (2H, br s), 2.69(2H, s), 3.92 (3H, s), 6.24-6.32 (1H, m), 6.61 (1H, s), 6.61 (1H, ddd,J=9.2, 1.4, 0.8 Hz), 7.34-7.43 (2H, m), 7.78 (1H, ddd, J=6.8, 2.2, 0.8Hz), 7.93 (1H, dd, J=1.4, 0.6 Hz), 8.61 (1H, dd, J=5.0, 0.6 Hz).

Example 388

[3319]4-(3,4,8,9-Tetrahydro-6-methoxy-3-3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2(1H)-pyridinone

[3320] A solution of4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)pyridine1-oxide (0.90 g. 2.55 mmol) in acetic anhydride (5 mL) was heated underreflux for 20 hours. The reaction mixture was dissolved in methanol (100mL), conc. aqueous ammonia (20 mL) was added thereto and the mixture wasstirred at room temperature for 30 minutes. The reaction solvent wasconcentrated and distilled off under reduced pressure, and the residuewas combined with water. The organic material was extracted withchloroform, and the extract was washed with brine, dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas subjected to a column chromatography on a basic silica gel(chloroform followed by 2% methanol/chloroform), and recrystallized fromethyl acetate-hexane to obtain the title compound (0.52 g,

[3321] Yield: 58%).

[3322] Melting point: 232-233° C.

[3323]¹H NMR (CDCl₃) δ1.24 (6H, s), 1.40 (6H, s), 2.63 (2H, s), 2.69(2H, s), 3.92 (3H, s), 6.35 (1H, dd, J=6.6, 1.4 Hz), 6.60 (1H, d, J=1.4Hz), 6.61 (1H, s), 7.43 (1H, d, J=6.6 Hz), 11.42 (1H, br s).

Example 389

[3324]1-(4-Pyridinylmethyl)-4-(3,4,8,9-tetrahydro-6-methoxy-3;3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2(1H)-pyridinone

[3325] Sodium hydride (60% dispersion in oil) (0.360 g, 9.00 mmol) wasadded to a suspension of4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2(1H)-pyridinone(1.06 g, 3.00 mmol) in N,N-dimethylformamide (15 mL) with cooling in iceand the mixture was stirred at room temperature for 30 minutes.4-(Chloromethyl)pyridine hydrochloride (0.738 g, 4.50 mmol) was added tothe mixture and the mixture was stirred at room temperature further for1 hour. The reaction solvent was concentrated and distilled off underreduced pressure and the residue was combined with water. The organicmaterial was extracted with ethyl acetate, washed with brine, dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresidue was subjected to a column chromatography on a basic silica gel(hexane/ethyl acetate 1:1 followed by ethyl acetate), and recrystallizedfrom ethyl acetate-hexane to obtain the title compound (0.41 g, Yield:31%).

[3326] Melting point: 171-172° C.

[3327]¹H NMR (CDCl₃) δ1.24 (6H, s), 1.40 (6H, s), 2.65 (2H, s), 2.67(2H, s), 3.92 (3H, s), 5.18 (2H, br s), 6.28(1H, dd, J=7.0, 1.8 Hz),6.61 (1H, s), 6.65 (1H, d, J=1.8 Hz), 7.18 (2H, d, J=6.0 Hz), 7.32 (1H,d, J=7.0 Hz), 8.58 (2H, d, J=6.0 Hz).

Example 390

[3328]1-(2-Methoxyethyl)-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2(1H)-pyridinone

[3329] The title compound was obtained from 2bromoethyl methyl ether bythe method similar to that in EXAMPLE 389. Yield: 38%.

[3330] Melting point: 85-87° C. (hexane-ethyl acetate).

[3331]¹H NMR (CDCl₃) δ1.23 (6H, s), 1.39 (6H, s), 2.63 (2H, s), 2.67(2H, s), 3.31 (3H, s), 3.66 (2H, t, J=5.0 Hz), 3.92 (3H, s), 4.15 (2H,br s), 6.18 (1H, dd, J=7.0, 1.8 Hz), 6.58 (1H, d, J=1.8 Hz), 6.60 (1H,s), 7.39 (1H, d, J=7.0 Hz).

Example 391

[3332]1-(2-Pyridinylmethyl)-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2(1H)-pyridinone

[3333] The title compound was obtained from 2-(chloromethyl)pyridinehydrochloride by the method similar to that in EXAMPLE 389. Yield: 57%.

[3334] Melting point: 165-166° C. (ethyl acetate-hexane).

[3335]¹H NMR (CDCl₃) δ1.22 (6H, s), 1.38 (6H, s), -2.63 (2H, s), 2.66(2H, s), 3.91 (3H, s), 5.26 (2H, br s), 6.23 (1H, dd, J=7.0, 1.8 Hz),6.58 (1H, d, J,=1.8 Hz), 6.59 (1H, s), 7.18-7.25 (1H, m), 7.42 (1H, d,J=7.6 Hz), 7.58 (1H, d, J=7.0 Hz), 7.66 (1H, td, J=7.6, 1.8 Hz), 8.53(1H, d, J=4.8 Hz).

Example 392

[3336]2-Oxo-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-1(2H)-pyridineacetamide

[3337] The title compound was obtained as a main product from2-chloroacetamide by the method similar to that in EXAMPLE 389.

[3338] Yield: 56%.

[3339] Melting point: 251-252° C. (ethyl acetate-methanol).

[3340]¹H NMR (CDCl₃) δ1.13 (6H, s), 1.29 (6H, s), 2.61 (4H, s), 3.81(3H, s), 4.55 (2H, s), 6.14 (1H, dd, J=7.0, 1.8 Hz), 6.22 (1H, d, J=1.8Hz), 6.80 (1H, s), 7.20 (1H, br s), 7.61 (1H, d, J=7.0 Hz), 7.65 (1H, brs).

Example 393

[3341]N-(2-Amino-2-oxoethyl)-2-oxo-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-1(2H)-pyridineacetamide

[3342] Similarly to EXAMPLE 392, the title compound was obtained as aby-product. Yield: 10%.

[3343] Melting point: 166-168° C. (ethyl acetate).

[3344]¹H NMR (CDCl₃) δ1.13 (6H, s), 1.29 (6H, s), 2.61 (4H, s), 3.68(2H, d, J=5.6 Hz), 3.81 (3H, s), 4.63 (2H, s), 6.19 (1H, dd, J=6.8, 1.8Hz), 6.25 (1H, d, J=1.8 Hz), 6.80 (1H, s), 7.14 (1H, br s), 7.30 (1H, brs), 7.66 (1H, d, J=6.8 Hz), 8.47 (1H, t, J=5.6 Hz).

Example 394

[3345]1-(3-Pyridinylmethyl)-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2(1H)-pyridinone

[3346] The title compound was obtained from 3-(chloromethyl)pyridinehydrochloride by the method similar to that In EXAMPLE 389. Yield: 56%.

[3347] Melting point: 126-128° C. (ethyl acetate-hexane).

[3348]¹H NMR (CDCl₃) δ1.22 (6H, s), 1.39 (6H, s), 2.63 (2H, s), 2.66(2H, s), 3.92 (3H, s), 5.19 (2H, br s), 6.25 (1H, dd, J=6.8, 1.8 Hz),6.60 (1H, s), 6.62 (1H, d, J=1.8 Hz), 7.28 (1H, dd, J=8.0, 4.8 Hz), 7.35(1H, d, J=6.8 Hz), 7.72 (1H, d, J=8.0 Hz), 8.57 (1H, dd, J=4.8, 1.6 Hz),8.61 (1H, d, J=1.6 Hz).

Example 395

[3349]1-Methyl-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2(1H)-pyridinone

[3350] The title compound was obtained from iodomethane by the methodsimilar to that in EXAMPLE 389. Yield: 62%.

[3351] Melting point: 180-181° C.

[3352]¹H NMR (CDCl₃) δ1.22 (6H, s), 1.40 (6H, s), 2.64 (2H, s), 2.66(2H, s), 3.58 (3H, s), 3.92 (3H, s), 6.23 (1H, dd, J=7.0, 1.8 Hz), 6.58(1H, d, J=1.8 Hz), 6.60 (1H, s), 7.33 (1H, d, J=7.0 Hz).

Example 396

[3353]1-(2-Quinolinylmethyl)-4-(3,4,8,9-tetrahydro-⁶-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2(1H)-pyridinone

[3354] The title compound was obtained from 2-(chloromethyl)quinolinehydrochloride by the method similar to that in EXAMPLE 389. Yield: 55%.

[3355] Melting point: 189-190° C. (ethyl acetate-hexane).

[3356]¹H NMR (CDCl₃) δ1.22 (6H, s), 1.37 (6H, s), 2.65 (4H, s), 3.91(3H, s), 5.47 (2H, br s), 6.24 (1H, dd, J=6.8, 1.8 Hz), 6.59 (1H, s),6.63 (1H, d, J=1.8 Hz), 7.51 (1H, d, J=8.4 Hz), 7.49-7.59 (1H, m), 7.60(1H, d, J=6.8 Hz), 7.68-7.77 (1H, m), 7.82 (1H, d, J=8.4 Hz), 8.03 (1H,d, J=8.4 Hz), 8.14 (1H, d, J=8.4 Hz).

Example 397

[3357] 2-[2-[2-Oxo-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-1(2H)-pyridinyl]ethyl]-1H-isoindole-1,3(2H)-dione

[3358] The title compound was-obtained from N-(2-bromoethyl)phthalimideby the method similar to that in EXAMPLE 389. Yield: 14%.

[3359] Melting point: 226-228° C. (ethyl acetate-methanol).

[3360]¹H NMR (CDCl₃) δ1.19 (6H, s), 1.50 (6H, s), 2.65 (2H, s), 2.71(2H, s), 3.92 (3H, s), 4.13 (2H, br s), 4.26 (2H, br s), 6.15 (1H, dd,J=7.0, 1.8 Hz), 6.51 (1H, d, J=1.8 Hz), 6.58 (1H, s), 7.14 (1H, d, J=7.0Hz), 7.72-7.84 (4H, m).

Example 398

[3361]1-[2-(Dimethylamino)ethyl]-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2(1H)-pyridinone

[3362] The title compound was obtained from 2-(dimethylamino)ethylchloride hydrochloride by the method similar to that in EXAMPLE 389.Yield: 9%.

[3363] Melting point: 111-113° C. (ethyl acetate-hexane).

[3364]¹H NMR (CDCl₃) δ1.23 (6H, s), 1.38 (6H, s), 2.28 (6H, s), 2.62(2H, t, J=6.6 Hz), 2.63 (2H, s), 2.67 (2H, s), 3.92 (3H, s), 4.05 (2H,t, J=6.6 Hz), 6.19 (1H, dd, J=7.0, 1.8 Hz), 6.56 (1H, d, J=1.8 Hz), 6.60(1H, s), 7.35 (1H, d, J=7.0 Hz).

Example 399

[3365]1-(Phenylmethyl)-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2(1H)-pyridinone

[3366] The title compound was obtained from benzyl bromide by the methodsimilar to that in EXAMPLE 389. Yield: 68%.

[3367] Melting point: 170-172° C. (ethyl acetate-hexane).

[3368]¹H NMR (CDCl₃) δ1.22 (6H, s), 1.38 (6H, s), 2.63 (2H, s), 2.66(2H, s), 3.91 (3H, s), 5.18 (2H, br s), 6.19 (1H, dd, J=7.0, 1.8 Hz),6.59 (1H, s), 6.62 (1H, d, J=1.8 Hz), 7.30-7.33 (6H, m).

Example 400

[3369]4-[[2-Oxo-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-1(2H)-pyridinyl]methyl]benzoicacid methyl ester

[3370] The title compound was obtained from 4-(bromomethyl)benzoic acidmethyl ester by the method similar to that in EXAMPLE 389. Yield: 73%.

[3371] Melting point: 193-194° C. (ethyl acetate-hexane).

[3372]¹H NMR (CDCl₃) δ1.23 (6H, s), 1.39 (6H, s), 2.64 (2H, s), 2.67(2H, s), 3.92 (6H, s), 5.23 (2H, br s), 6.24 (1H, dd, J=7.0, 1.8 Hz),6.60 (1H, s), 6.63 (1H, d, J=1.8 Hz), 7.32 (1H, d, J=7.0 Hz), 7.36 (2H,d, J=8.4 Hz), 8.01 (2H, d, J=8.4 Hz).

Example 401

[3373]N-(2-Hydroxyethyl)-4-[[2-oxo-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-1(2H)-pyridinyl]methyl]benzamide

[3374] A solution of4-[[2-oxo-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-1(2H)-pyridinyl]methyl]benzoicacid methyl ester (1.32 g, 2.64 mmol) and 2-aminoethanol (2 mL, 33.1mol) in xylene (10 mL) was heated under reflux for 7 hours. The reactionmixture was combined with ice water and extracted twice with chloroform.The combined organic layer was washed with water and brine, dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresidue was subjected to a column chromatography on a basic silica gel(ethyl acetate/methanol 19:1 followed by 9:1), and recrystallized fromethyl acetate-methanol to obtain the title compound (0.81 g, Yield:58%).

[3375] Melting point: 220-222° C.

[3376]¹H NMR (CDCl₃) δ1.22 (6H, s), 1.40 (6H, s), 2.64 (2H, s), 2.66(2H, s), 3.48-3.59 (3H, m), 3.76 (2H, t, J=5.0 Hz), 3.92 (3H, 8), 5.18(2H, br s), 6.26 (1H, dd, J=7.0, 1.8 Hz), 6.60 (¹H, s), 6.63 (1H, d,J=1.8 Hz), 7.07 (1H, br t, J=5.5 Hz), 7.30 (2H, d, J=8.4 Hz), 7.35 (1H,d, J=7.0 Hz), 7.74 (2H, d, J=8.4 Hz).

Example 402

[3377]4-[[2-Oxo-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-1(2H)-pyridinyl]methyl]-N-(4-pyridinyl)benzamide

[3378]4-[[2-Oxo-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-1(2H)-pyridinyl]methyl]benzoicacid methyl ester (2.78 g, 5.55 mol) was dissolved in 1 M aqueoussolution of sodium hydroxide (30 mL) and the mixture was heated underreflux for 30 minutes. The reaction mixture was cooled to roomtemperature, and 2 M hydrochloric acid (30 mL) was added thereto. Thesolvent was concentrated and distilled off under reduced pressure, anddiluted with ethanol. The resultant insolubles were filtered off, andethanol was concentrated and distilled off under the reduced pressure.This procedure-was repeated twice -to obtain4-[[2-oxo-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-1(2H)-pyridinyl]methyl]benzoicacid hydrochloride (2.90 g, quantitative).1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.483 g,2.52 mmol) was added to a solution of the resultant4-[[2-oxo-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-1(2H)-pyridinyl]methyl]benzoicacid hydrochloride (1.20 g, 2.29 mmol), 4-aminopyridine (0.259 g, 2.75mmol) and 1-hydroxy-1H-benzotriazole monohydrate (0.701 g, 4.58 mmol) inN,N-dimethylformamide (10 mL) with cooling in ice, and stirred at thesame temperature for 1 hour and then at room temperature for 30 hours.The reaction solvent was concentrated and distilled off under reducedpressure, and to the residue an aqueous solution of sodium hydroxide waspoured. The organic material was extracted with ethyl-acetate, and theextract was washed with brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was subjected to acolumn chromatography on a basic silica gel (1% methanol/ethyl acetatefollowed by 2%) and recrystallized from ethyl acetate-hexane to obtainthe title compound (0.15 g, Yield: 12%).

[3379] Melting point: 144-146° C.

[3380]¹H NMR (CDCl₃) δ1.23 (6H, s), 1.39 (6H, s), 2.63 (2H, s), 2.67(2H, s), 3.92 (3H, s), 5.20 (2H, br s), 6.29 (1H, dd, J=6.8, 1.8 Hz),6.61 (2H, s), 7.32 (2H, d, J=8.4 Hz), 7.38 (1H, d, J=6.8 Hz), 7.70 (2H,dd, J=4.8, 1.8 Hz), 7.84 (2H, d, J=8.4 Hz), 8.51 (2H, dd, J=4.8, 1.8Hz), 9.06 (1H, br s).

Example 403

[3381]2-Oxo-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-1(2H)-pyridineaceticacid 1,1-dimethylethyl ester

[3382] The title compound was obtained from tert-butyl bromoacetate bythe method similar to that in EXAMPLE 389.

[3383] Yield: 80%.

[3384] Melting point: 166-168° C. (diethyl ether-hexane).

[3385]¹H NMR (CDCl₃) δ1.23 (6H, s), 1.40 (6H, s), 1.49 (9H, s), 2.67(2H, s), 2.68 (2H, s), 3.92 (3H, s), 4.57 (2H, s), 6.25 (1H, dd, J=7.0,1.8 Hz), 6.59 (1H, d, J=1.8 Hz), 6.59 (1H, s), 7.25 (1H, d, J=7.0 Hz).

Example 404

[3386]2-Oxo-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-1(2H)-pyridineaceticacid hydrochloride

[3387]2-Oxo-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-1(2H)-pyridineaceticacid 1,1-dimethylethyl ester (10.1 g, 21.6 mmol) was dissolved in 6 Mhydrochloric acid (25 mL) and the mixture was heated under reflux for 1hour. The reaction solution was cooled to room temperature, and thereaction solvent was concentrated and distilled off under reducedpressure to obtain the title compound (9.60 g, 99%).

[3388] Amorphous.

[3389]¹H NMR (CDCl₃) δ1.41 (6H, s), 1.53 (6H, s), 2.68 (2H, s), 2.98(2H, s), 3.98 (3H, s), 4.71 (2H, br s), 6.24 (1H, br s), 6.35 (1H, d,J=7.0 Hz), 6.70 (2H, s), 7.72 (1H, d, J=7.0 Hz).

Example 405

[3390]2-Oxo-N-(3-pyridinyl)-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-1(2H)-pyridineacetamide

[3391] 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(0.566 g, 2.95 mmol) was added to a solution of2-oxo-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-1(2H)-pyridineaceticacid hydrochloride (1.20 g, 2.68 mmol), 3-aminopyridine (0.303 g, 3.22mmol) and 1-hydroxy-1H-benzotriazole monohydrate (0.821 g, 5.36 mmol) inN,N-dimethylformamide (10 mL) with cooling in ice, and the mixture wasstirred at the same temperature for 1 hour and then at room temperaturefor 3 hours. The reaction solvent was concentrated and distilled offunder reduced pressure, and to the residue an aqueous solution of sodiumhydroxide was poured. The organic material was extracted with ethylacetate, and the extract was washed with brine, dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas subjected to a column chromatography on a basic silica gel (5%methanol/ethyl acetate) and recrystallized from ethyl acetate-methanolto obtain the title compound (0.51 g, Yield: 39%).

[3392] Melting point: 251-253° C.

[3393]¹H NMR (CDCl₃) δ1.23 (6H, s), 1.40 (6H, s), 2.63 (2H, s), 2.68(2H, s), 3.93 (3H, s), 4.80 (2H, br s), 6.42 (1H, dd, J=7.0, 1.8 Hz),6.62 (1H, s), 6.75 (1H, d, J=1.8 Hz), 7.20 (1H, dd, J=8.4, 4.6 Hz), 7.52(1H, d, J=7.0 Hz), 7.94 (1H, ddd, J=8.4, 1.8, 1.4 Hz), 8.31 (1H, dd,J=4.6, 1.4 Hz), 8.64 (1H, d, J=1.8 Hz), 9.82 (1H, br s).

Example 406

[3394]2-Oxo-N-(5-quinolinyl)-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-1(2H)-pyridineacetamide

[3395] The title compound was obtained-from 5-aminoquinoline by themethod similar to that in EXAMPLE 405. Yield: 10%.

[3396] Melting point: 136-138° C. (ethyl acetate-hexane).

[3397]¹H NMR (CDCl₃) δ1.22 (6H, s), 1.31 (6H, s), 2.59 (2H, s), 2.66(2H, s), 3.92 (3H, s), 4.89 (2H, br s), 6.48 (1H, dd, J=6.8, 1.8 Hz),6.61 (1H, s), 6.80 (1H, d, J=1.8 Hz), 7.47 (1H, dd, J=8.8, 4.0 Hz), 7.58(1H, d, J=6.8 Hz), 7.70 (1H, t, J=8.4 Hz), 7.93 (1H, d, J=8.4 Hz), 8.21(1H, d, J=8.8 Hz), 8.47 (1H, d, J=8.4 Hz), 8.93 (1H, dd, J=4.0, 1.2 Hz),10.21 (1H, br s).

Example 407

[3398]1-(2-Quinolinyl)-5-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2(1H)-pyridinone

[3399] 25% Hydrogen bromide/acetic acid solution (1 mL) was added to asolution of1-(6-chloro-3-pyridinyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinoline(0.78 g, 2.10 mmol) and quinoline 1-oxide monohydrate (3.05 g, 21.0mmol) in toluene (5 mL) and acetic acid (5 mL) and the mixture washeated under reflux for 20 hours. The reaction mixture was combined withice water, and the aqueous layer was neutralized with conc. aqueousammonia, and extracted twice with ethyl acetate. The combined organiclayer was washed with water and brine, dried over sodium sulfate,filtered and concentrated under reduced pressure. The residue wassubjected to a column chromatography on a basic silica gel (hexane/ethylacetate 2:1) and recrystallized from ethyl acetate to obtain the titlecompound (0.41 g, Yield: 41%).

[3400] Melting point: 191-192° C.

[3401]¹H NMR (CDCl₃) δ1.21 (6H, s), 1.52 (6H, s), 2.65 (2H, s), 2.98(2H, s), 3.94 (3H, s), 6.62 (1H, s), 6.74 (1H, d, J=9.2 Hz), 7.55-7.63(1H, m), 7.64 (1H, dd, J=9.2, 2.6 Hz), 7.69-7.77 (1H, m), 7.88 (1H, dd,J=8.0, 1.4 Hz), 7.92 (1H, d, J=8.8 Hz), 8.04 (1H, dd, J=8.0, 1.4 Hz),8.12 (1H, d, J=2.2 Hz), 8.26 (1H, d, J=8.8 Hz).

Example 408

[3402]1-(1-Isoquinolinyl)-5-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2(1H)-pyridinone

[3403] The title compound was obtained from isoquinoline 2-oxide by themethod similar to that in EXAMPLE 407. Yield: 40%.

[3404] Melting point: 147-149° C. (ethyl acetate-hexane).

[3405]¹H NMR (CDCl₃) δ1.16 (3H, s), 1.23 (3H, s), 1.41 (3H, s), 1.55(3H, s), 2.63 (2H, s), 2.75 (1H, d, J=16.0 Hz), 3.22 (1H, d, J=16.0 Hz),3.90 (3H, s), 6.58 (1H, s), 6.78 (1H, d, J=9.6 Hz), 7.62-7.80 (6H, m),7.92 (1H, d, J=8.4 Hz), 8.46 (1H, d, J=5.8 Hz).

Example 409

[3406]1-[4-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-pyridinyl]-2(1H)-quinolinone

[3407] A solution of4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)pyridine1-oxide (0.95 g, 2.7 mmol), 2-chloroquinoline (1.8 g, 11 mmol), 25%.hydrogen bromide/acetic acid solution (0.7 mL) and acetic acid (6.0 mL)in toluene (8.8 mL) was heated under reflux for 1 hour. The reactionsolution was cooled to room temperature, and the reaction mixture waspoured into water. After the mixture was made-weakly alkaline with conc.aqueous ammonia, the organic material was extracted with ethyl acetate.The extract was washed with brine and dried over sodium sulfate, andthen the solvent was distilled off under reduced pressure. The resultantresidue was purified by a column chromatography on a basic silica gel(ethyl acetate/hexane 2:1 followed by 1:1) to obtain crude crystals. Theresultant crude crystals were recrystallized from ethyl acetate-hexaneto obtain the title compound (0.72 g, Yield: 56%).

[3408] Melting point: 190-191° C.

[3409]¹H NMR (DMSO-₆) δ1.18 (6H, s), 1.24 (6H, s), 2.51 (2H, s), 2.67(2H, s), 3.80 (3H, s), 6.48 (1H, d, J=8.8 Hz), 6.68 (1H, d, J=9.6 Hz),6.80 (1H, s), 7.26 (1H, t, J=7.2 Hz), 7.40-7.48 (2H, m), 7.64 (1H, dd,J=4.9, 1.6 Hz), 7.79 (¹H, d, J=7.6 Hz), 8.05 (1H, d, J=9.6 Hz), 8.80(1H, d, J=4.9 Hz).

Example 410

[3410]1,6-Dihydro-6-oxo-1-[4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-pyridinyl]-3-pyridinecarboxamide

[3411] The title compound was obtained from 6-chloronicotinamide by themethod similar to that in EXAMPLE 409.

[3412] Yield: 31%.

[3413] Amorphous.

[3414]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.38 (6H, s), 2.05 (2H, s), 2.69(2H, s), 3.93 (3H, s), 6.12 (2H, br), 6.59 (1H, d, J=9.6 Hz), 6.62 (1H,s), 7.42 (1H, d, J=5.0 Hz), 7.78 (1H, dd, J=9.6, 2.6 Hz), 7.90 (1H, s),8.49 (1H, d, J=2.6 Hz), 8.59 (1H, d, J=5.0 Hz).

Example 411

[3415]1-(2-Chloro-4-pyridinyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinoline

[3416] A solution of4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)pyridine1-oxide (2.4 g, 6.8 mmol) in phosphorus oxychloride (20 mL, 210 mmol)was heated under reflux for 30 minutes. The reaction solution was cooledto room temperature, and then poured into ice water. After the mixturewas made alkaline with an aqueous solution of sodium hydroxide, theorganic material was extracted with ethyl acetate. The extract waswashed with brine and dried over sodium sulfate, and then the solventwas distilled off under reduced pressure. The resultant residue waspurified by a column chromatography on a basic silica gel (hexane/ethylacetate 5:1 followed by 3:1) to obtain crude crystals. The crudecrystals were recrystallized from ethyl acetate-hexane to obtain, as amain product, the title compound (0.84 g, Yield: 33%).

[3417] Melting point: 139-140° C.

[3418]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.37 (6H, s), 2.30 (2H, s), 2.70(2H, s), 3.93 (3H, s), 6.64 (1H, s), 7.27 (1H, dd, J=5.2, 0.8 Hz), 7.43(1H, d, J=0.8 Hz), 8.44 (1H, d, J=5.2 Hz).

Example 412

[3419]1-(3-Chloro-4-pyridinyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinoline

[3420] Similarly to EXAMPLE 411, the title compound was obtained as aby-product. Yield: 8%.

[3421] Melting point: 126-128° C. (hexane).

[3422]¹H NMR (CDCl₃) δ1.23 (3H, s), 1.30 (3H, s), 1.35 (3H, s), 1.38(3H, s), 2.05 (2H, s), 2.69 (1H, d, J=15.7 Hz), 2.80 (1H, d, J=15.7 Hz),3.92 (3H, s), 6.62 (1H, s), 7.31 (1H, d, J=4.8 Hz), 8.58 (1H, d, J=4.8Hz), 8.63 (1H, s).

Example 413

[3423]2-[2-Oxo-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-1(2H)-pyridinyl]-4-pyridinecarboxamide

[3424] A solution of1-(2-chloro-4-pyridinyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinoline(1.0 g, 2.7 mmol), 4-pyridinecarboxamide 1-oxide (2.9 g, 21 mmol), 25%hydrogen bromide/acetic acid solution (1.0 mL) and acetic acid (5.6 mL)in xylene (10 mL) was heated under reflux for 9 hours. The reactionsolution was cooled to room temperature, and the reaction mixture waspoured into water. After the mixture was made weakly alkaline with 8 Maqueous solution of sodium hydroxide, the organic material was extractedwith ethyl acetate. The extract was washed with brine and dried oversodium sulfate, and then the solvent was distilled off under reducedpressure. The resultant residue was purified by a column chromatographyon a basic silica gel (chloroform/methanol 50:1 followed by 20:1) toobtain crude crystals. The resultant crude crystals were recrystallizedfrom ethyl acetate-diisopropyl ether to obtain the title compound (0.22g, Yield: 17%).

[3425] Melting point: 174-175° C.

[3426]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.43 (6H, s), 2.69 (2H, s), 2.76(2H, s), 3.93 (3H, s), 6.12 (1H, br), 6.43 (1H, d, J=7.3 Hz), 6.63 (1H,s), 6.68 (1H, s), 7.16-7.39 (1H, br), 7.78 (1H, d, J=4.4 Hz), 8.01 (1H,d, J=7.3 Hz), 8.33 (¹H, s), 8.67 (1H, d, J=4.4 Hz).

Example 414

[3427]1-(2-Pyridinyl)-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2(1H)-pyridinone

[3428] The title compound was obtained from pyridine 1-oxide by themethod similar to that in EXAMPLE 413. Yield: 56%.

[3429] Amorphous.

[3430]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.42 (6H, s), 2.69 (2H, s), 2.78(2H, s), 3.93 (3H, s), 6.39 (1H, dd, J=7.1, 1.8 Hz), 6.62-6.67 (2H, m),7.30-7.37 (1H, m), 7.80-7.89 (1H, m), 7.96-8.00 (2H, m), 8.57-8.60 (1H,m).

Example 415

[3431]1-(2-Quinolinyl)-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2(1H)-pyridinone

[3432] The title compound was obtained from quinoline 1-oxide by themethod similar to that in EXAMPLE 413. Yield: 24%.

[3433] Melting point: 175-176° C. (ethyl acetate-hexane).

[3434]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.44 (6H, s), 2.70 (2H, s), 2.82(2H, s), 3.94 (3H, s), 6.45 (1H, dd, J=7.4, 1.8 Hz), 6.63 (1H, s), 6.70(1H, d, J=1.4 Hz), 7.61 (1H, td, J=7.6, 1.2 Hz), 7.77 (1H, td, J=8.4,1.4Hz), 7.90 (1H, d, J=8.4 Hz), 7.99-8.16 (3H, m), 8.27 (1H, d, J=8.8Hz).

Example 416

[3435]3,4,8,9-Tetrahydro-6-methoxy-1-(4-methoxyphenyl)-3,3-dimethylfuro[2,3-h]isoquinoline

[3436] The title compound was obtained from 4-aminonitrile and2,3-dihydro-7-methoxy-5-(2-methyl-1-propenyl)benzofuran by the methodsimilar to that in EXAMPLE 1. Yield: 49%.

[3437] Melting point: 147-148° C. (ethyl acetate-hexane).

[3438]¹H NMR (CDCl₃) δ1.23 (6H, s), 2.46 (2H, t, J=8.8 Hz), 2.68 (2H,s), 3.87 (3H, s), 3.93 (3H, s), 4.37 (2H, t, J=8.8 Hz), 6.61 (1H, s),6.91 (2H, d, J=8.7 Hz), 7.34 (2H, d, J=8.7 Hz).

Example 417

[3439]3,4,8,9-Tetrahydro-6-methoxy-3,3,9,9-tetramethyl-1-phenylfuro[2,3-h]isoquinoline

[3440] The title compound was obtained from benzonitrile and2,3-dihydro-7-methoxy-3,3-dimethyl-5-(2-methyl-1-propenyl)benzofuran bythe method similar to that in EXAMPLE 1.

[3441] Yield: 1.4%.

[3442] Melting point: 142-143° C. (hexane-diethyl ether).

[3443]¹H NMR (CDCl₃) δ0.78 (6H, s), 1.18 (6H, s), 2.61 (2H, s), 3.93(3H, s), 4.03 (2H, s), 6.65 (1H, s), 7.32-7.44 (5H, m).

Example 418

[3444]3,3-Diethyl-3,4,8,9-tetrahydro-6-methoxy-8,8-dimethyl-1-phenylfuro[2,3-h]isoquinolinehydrochloride

[3445] The title compound was obtained from benzonitrile and5-(2-ethyl-1-butenyl)-2,3-dihydro-7-methoxy-2,2-dimethylbenzofuran bythe method similar to that in EXAMPLE 306.

[3446] Yield: 36%.

[3447] Melting point: 178-179° C. (ethyl acetate).

[3448]¹H NMR (CDCl₃) δ1.07 (6H, t, J=7.8 Hz), 1.33 (6H, s), 1.94-2.18(4H, m), 2.22 (2H, s), 3.07 (2H, s), 4.01 (3H, s), 6.76 (1H, s),7.57-7.67 (5H, m).

Example 419

[3449]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-furo[2,3-h]isoquinolinecarboxylicacid methyl ester

[3450] The title compound was obtained from methyl cyanoformate by themethod similar to that in EXAMPLE 1. Yield: 16%.

[3451] Melting point: 161-162° C. (chloroform-hexane).

[3452]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.49 (6H, s), 2.65 (2H, s), 2.94(2H, s), 3.91 (3H, s), 3.93 (3H, s), 6.55 (1H, s).

Example 420

[3453]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-furo[2,3-h]isoquinolinecarboxylicacid hydrochloride

[3454] 5 M aqueous solution of sodium hydroxide was added to a solutionof3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-furo[2,3-h]isoquinolinecarboxylicacid methyl ester (1.49 g, 4.69 mmol) in methanol (5 mL) and the mixturewas stirred at 60° C. for 5 hours. The reaction solution was made acidicwith 5 M hydrochloric acid, and concentrated under reduced pressure. Theresidue was combined with ethanol and the mixture was filtered, and thefiltrate was concentrated under reduced pressure, and this procedure wasrepeated three times to obtain the title compound (1.50 g, Yield: 94%).

[3455] Amorphous.

[3456]¹H NMR (DMSO-d₆) δ1.35 (6H, s), 1.41 (6H, s), 3.02 (2H, s), 3.17(2H, s), 3.91 (3H, s), 6.99 (1H, s).

Example 421

[3457]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-N-[2-(4-pyridinyl)ethyl]-1-furo[2,3-h]isoquinolinecarboxamide

[3458] The title compound was obtained from3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-furo[2,3-h]isoquinolinecarboxylicacid hydrochloride and 4-(2-aminoethyl)pyridine by the method similar tothat in Example 159. Yield: 42%.

[3459] Melting point: 160-161° C. (diisopropyl ether-hexane).

[3460]¹H NMR (CDCl₃) δ1.15 (6H, s), 1.47 (6H, s), 2.59 (2H, s), 2.93(2H, t, J=7.0 Hz), 3.02 (2H, s), 3.68 (2H, q, J=7.0 Hz), 3.89 (3H, s),6.52 (1H, s), 6.93-7.02 (1H, m), 7.22 (2H, d, J=6.0 Hz), 8.55 (2H, d,J=6.0 Hz).

Example 422

[3461]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-N-phenyl-1-furo[2,3-h]isoquinolinecarboxamide

[3462] The title compound was obtained from3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-furo[2,3-h]isoquinolinecarboxylicacid hydrochloride and aniline by the method similar to that in EXAMPLE159. Yield: 60%.

[3463] Melting point: 175-176° C. (ethyl acetate-hexane).

[3464]¹H NMR (CDCl₃) δ1.22 (6H, s), 1.48 (6H, s), 2.63 (2H, s), 3.21(2H, s), 3.91 (3H, s), 6.55 (1H, s), 7.14 (1H, t, J=7.4 Hz), 7.38 (2H,d, J=7.4 Hz), 7.68 (2H, d, J=7.4 Hz), 8.84 (1H, s).

Example 423

[3465]N-(1-Azabicyclo[2.2.2-h]oct-3-yl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-furo[2,3-h]isoquinolinecarboxamide

[3466] The title compound was obtained from3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-furo[2,3-h]isoquinolinecarboxylicacid hydrochloride and 3-amino-1-azabicyclo[2.2.2-h]octane by the methodsimilar to that in EXAMPLE 159. Yield: 60%.

[3467] Melting point: 139-142° C. (ethyl acetate-hexane).

[3468]¹H NMR (CDCl₃) δ1.17 (3H, s), 1.19 (3H, s), 1.48 (6H, s),1.62-1.86 (4H, m), 2.02-2.10 (1H, m), 2.58-2.66 (1H, m), 2.59 (2H, s),2.80-2.98 (4H, m), 3.14 (2H, s), 3.35-3.49 (1H, m), 3.89 (3H, s),3.97-4.08 (1H, m), 6.52 (1H, s), 6.96 (1H, d, J=7.2 Hz).

Example 424

[3469]3,4,8,9-Tetrahydro-6-methoxy-3,3-dimethyl-1-(2-thienyl)furo[2,3-h]isoquinoline

[3470] The title compound was obtained from2,3-dihydro-7-methoxy-5-(2-methyl-1-propenyl)benzofuran and2-thiophenecarbonitrile by the method similar-to that in EXAMPLE 368.Yield: 23%.

[3471] Melting point: 122-125° C. (hexane).

[3472]¹H NMR (CDCl₃) δ1.23 (6H, s), 2.67 (2H, s), 2.73 (2H, t, J=8.6Hz), 3.93 (3H, s), 4.43 (2H, t, J=8.6 Hz), 6.60 (1H, s), 7.01-7.09 (2H,m), 7.35 (1H, dd, J=5.0, 1.4 Hz).

Example 425

[3473]3′,4′-Dihydro-6′-methoxy-3′,3′-dimethyl-1′-phenylspiro[cyclopentane-1,8(9′H)-furo[2,3-h]isoquinoline]

[3474] A solution of benzonitrile (0.700 g, 6.50 mmol) in toluene (5 mL)and acetic acid (5 mL) was treated dropwise with conc. sulfuric acid(0.6 mL) with cooling in ice. The ice bath was removed, and a solutionof7-methoxy-5-(2-methyl-1-propenyl)spiro[benzofuran-2(3H),1′-cyclopentane](1.29g, 5.00 mmol) in toluene (5 mL) was added to the mixture and the mixturewas stirred at 80° C. for 1 hour. The reaction mixture was combined withice, and the aqueous layer was neutralized with conc. aqueous ammonia,and extracted twice with ethyl acetate. The combined organic layer waswashed with water and brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was subjected to acolumn chromatography on a basic silica gel (hexane/ethyl acetate 10:1)and recrystallized from ethyl acetate-hexane to obtain the titlecompound (0.87 g, Yield: 48%).

[3475] Melting point: 130-131° C.

[3476]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.43-2.05 (8H, m), 2.32 (2H, s),2.69 (2H, s), 3.91 (3H, s), 6.60 (1H, s), 7.38 (5H, s).

Example 426

[3477]3′,4′-Dihydro-6′-methoxy-3′,3′-dimethyl-1′-(2-thienyl)spiro[cyclopentane-1,8(9′H)-furo[2,3-h]isoquinoline]

[3478] The title compound was obtained from 2-thiophenecarbonitrile bythe method similar to that in EXAMPLE 425. Yield: 28%.

[3479] Melting point: 142-143° C. (ethyl acetate-hexane).

[3480]¹H NMR (CDCl₃) δ1.22 (6H, s), 1.54-2.10 (8H, m), 2.65 (2H, s),2.67 (2H, s), 3.92 (3H, s), 6.59 (1H, s), 7.03 (1H, dd, J=5.0, 3.6 Hz),7.07 (1H, dd, J=3.6, 1.4 Hz), 7.35 (1H, dd, J=5.0, 1.4 Hz).

Example 427

[3481]4-[3′,4′-Dihydro-6′-methoxy-3′,3′-dimethylspiro[cyclopentane-1,8′(9′H)-furo[2,3-h]isoquinoline]-1′-yl]pyridine1-oxide

[3482] The title compound was obtained from 4-cyanopyridine 1-oxide bythe method similar to that in EXAMPLE 425. Yield: 12%.

[3483] Melting point: 205-207° C. (ethyl acetate-hexane).

[3484]¹H NMR (CDCl₃) δ1.23 (6H, s), 1.47-2.09 (8H, m), 2.56 (2H, s),2.67 (2H, s), 3.92 (3H, s), 6.62 (1H, s), 7.39 (2H, d, J=5.0 Hz), 8.24(2H, d, J=5.0 Hz).

Example 428

[3485]8,8-Diethyl-3,4,8,9-tetrahydro-6-methoxy-3,3-dimethyl-1-phenylfuro[2,3-h]isoquinolinehydrochloride

[3486] A solution of benzonitrile (0.670 g, 6.50 mmol) in toluene (5 mL)and acetic acid (5 mL) was treated dropwise with conc. sulfuric acid(0.6 mL) with cooling in ice. The ice bath was removed, and a solutionof 2,2-diethyl-2,3-dihydro-7-methoxy-5-(2-methyl-1-propenyl)benzofuran(1.30 g, 5.00 mmol) in toluene (5 mL) was added to the mixture and themixture was stirred at 80° C. for 1 hour. The reaction mixture wascombined with ice, and the aqueous layer was neutralized with conc.aqueous ammonia, and extracted twice with ethyl acetate. The combinedorganic layer was washed with water and brine, dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas subjected to a column chromatography on a basic silica gel(hexane/ethyl acetate 10:1) to obtain a free base of the title compound.This was combined with 3.35 M hydrogen chloride/ethanol solution (9.61mL), and the mixture was concentrated under reduced pressure. Theresidue was crystallized from diethyl ether, and the crystals wererecrystallized from ethyl acetate to obtain the title compound (0.69 g,Yield: 35%).

[3487] Melting point: 167-169° C.

[3488]¹H NMR (CDCl₃) δ0.78 (6H, t, J=7.4 Hz), 1.58 (2H, q, J=7.4 Hz),1.60 (2H, q, J=7.4 Hz), 1.70 (6H, s), 2.20 (2H, s), 3.02 (2H, s), 4.02(3H, s), 6.73 (1H, s), 7.28-7.72 (5H, m).

EXAMPLE 429

[3489]8,8-Diethyl-3,4,8,9-tetrahydro-6-methoxy-3,3-dimethyl-1-(2-thienyl)furo[2,3-h]isoquinolinehydrochloride

[3490] The title compound was obtained from 2-thiophenecarbonitrile bythe method similar to that in EXAMPLE 428. Yield: 20%.

[3491] Melting point: 152-154° C. (ethyl acetate-diethyl ether).

[3492]¹H NMR (CDCl₃) δ0.84 (6H, t, J=7.4 Hz), 1.60-1.72 (4H, m), 1.66(6H, s), 2.56 (2H, s), 2.98 (2H, s), 4.02 (3H, s), 6.71 (1H, s), 7.29(1H, dd, J=4.8, 3.8 Hz), 7.81 (1H, dd, J=4.8, 1.2 Hz), 8.06 (1H, dd,J=3.8, 1.2 Hz).

Example 430

[3493]4-(8,8-Diethyl-3,4,8,9-tetrahydro-6-methoxy-3,3-dimethylfuro[2,3-h]isoquinolin-1-yl)pyridine1-oxide hydrochloride

[3494] The title compound was obtained from 4-cyanopyridine 1-oxide bythe method similar to that in EXAMPLE 428. Yield: 4%.

[3495] Melting point: 184-186° C. (ethyl acetate).

[3496]¹H NMR (CDCl₃) δ0.84 (6H, t, J=7.4 Hz), 1.60-1.73 (4H, m), 1.67(6H, s), 2.43 (2H, s), 3.03 (2H, s), 4.04 (3H, s), 6.75 (1H, s), 7.74(2H, d, J=6;8 Hz), 8.34 (2H, d, J=6.8 Hz).

Example 431

[3497]1-(6-Methyl-2-quinolinyl)-5-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2(1H)pyridinone

[3498] A solution ofN-[2-(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-1,1-dimethylethyl]-1,6-dihydro-1-(6-methyl-2-quinolinyl)-6-oxo-3-pyridinecarboxamide(0.70 g, 1.4 mmol) in phosphorus oxychloride (5.0 mL, 54 mmol) washeated under reflux for 4.5 hours. The reaction solution was cooled toroom temperature, and the reaction mixture was poured into water. Afterthe mixture was made weakly alkaline with 8 M aqueous solution of sodiumhydroxide, and the organic material was extracted with ethyl acetate.The extract was washed with brine and dried over sodium sulfate, andthen the solvent was distilled off under reduced pressure. The resultantresidue was purified by a column chromatography on a basic silica gel(hexane/ethyl acetate 2:1 followed by 1:1) to obtain crude crystals. Theresultant crude crystals were recrystallized from hexane-duisopropylether to obtain the title compound (0.13 g, Yield: 19%).

[3499] Melting point: 201-202° C. (hexane-diisopropyl ether).

[3500]¹H NMR (CDCl₃) δ1.21 (6H, s), 1.51 (6H, s), 2.56 (3H, s), 2.65(2H, s), 2.98 (2H, s), 3.94 (3H, s), 6.62 (1H, s), 6.73 (1H, d, J=9.4Hz), 7.55 (1H, dd, J=8.8, 1.8 Hz), 7.61-7.67 (2H, m), 7.87 (1H, d, J=8.8Hz), 7.92 (1H, d, J=8.6 Hz), 8.10 (1H, d, J=2.6 Hz), 8.16 (1H, d, J=8.8Hz).

Example 432

[3501]1-(6-Chloro-3-pyridinyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinoline

[3502] The title compound was obtained from6-chloro-N-[2-(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-1,1-dimethylethyl]-3-pyridinecarboxamideby the method similar to that in EXAMPLE 431. Yield: 40%.

[3503]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.36 (6H, s), 2.28 (2H, s), 2.70(2H, s), 3.93 (3H, s), 6.63 (1H, s),7.38 (1H, d, J=7.8 Hz), 7.74 (1H,dd, J=7.8, 2.2 Hz), 8.42 (1H, d, J=2.0 Hz).

Example 433

[3504][5-[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-1H-tetorazol-1-yl]methyl2,2-dimethylpropanoate

[3505] 3-(1H-Tetrazol-5-yl)benzonitrile (0.587 g, 3.4 mmol) wassuspended in toluene (5 mL) and acetic acid (5 mL). While cooling inice, conc. sulfuric acid (0.4 mL) followed by a solution of1-(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-2-methyl-1-propanol(0.751 g, 3.0 mmol) in toluene were added thereto and the mixture wasstirred at 80° C. for 3 hours. The reaction mixture was combined withice water, followed by an aqueous solution of sodium hydrogen carbonateto adjust at pH 4, and then extracted three times with tetrahydrofuran.The extract was washed with brine, dried over sodium sulfate, filteredand concentrated under reduced pressure. The residue was dissolved inN,N-dimethylformamide (5 mL), potassium carbonate (1.11 g, 8.0 mmol) andchloromethyl pivalate (1.04 mL, 7.2 mmol) were added thereto and themixture was stirred at room temperature for 18 hours. The reactionmixture was combined with ice, water and extracted twice with ethylacetate. The extract was washed with brine dried over sodium sulfate,filtered, and concentrated under reduced pressure. The residue wassubjected to a column chromatography on a silica gel, eluted withhexane/ethyl acetate (2:1) to collect the intended fraction, which wasconcentrated and recrystallized from diethyl ether/hexane (1:1) toobtain the title compound (0.122 g, yield: 7.8%).

[3506] Melting point: 134-136° C.

[3507]¹H NMR (CDCl₃) δ1.22 (9H, s), 1.26 (6H, s), 1.29 (6H, s), 2.25(2H, s), 2.72 (2H, s), 3.93 (3H, s), 6.52 (2H, s), 6.64 (1H, s), 7.5-8.3(4H, m).

Example 434

[3508]5-[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-1H-tetrazole-1-aceticacid sodium salt

[3509] 5-(3-Cyanophenyl)-1H-tetrazole-1-acetic acid methyl ester (0.730g, 3.0 mmol) was dissolved in toluene (5 mL) and acetic acid (5 mL),and, while cooling in ice, conc. sulfuric acid (0.4 mL) followed by asolution of1-(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-2-methyl-1-propanol(0.751 g, 3.0 mmol) in toluene were added thereto and the mixture wasstirred at 80° C. for 4 hours. The reaction mixture was combined withice water, and washed with diethyl ether. The aqueous layer was combinedwith aqueous solution of sodium hydrogen carbonate to adjust at pH 7,and subjected to a column chromatography on a polystyrene gel [MCI GELCHP20P (MITSUBISHI KASEI KOGYO)], eluted with ethanol/water (3:7) tocollect the intended fraction, which was concentrated to remove ethanol,and then freeze-dried to obtain the title compound (0.68 g, Yield: 47%).

[3510] Melting point: 180° C.

[3511]¹H NMR (DMSO-d₆) δ1.17 (6H, s), 1.19 (6H, s), 2.26 (2H, s), 2.67(2H, s), 3.82 (3H, s), 4.97 (2H, s), 6.83 (1H, s), 7.4-8.2 (4H, m).

Example 435

[3512]3,4,8,9-Tetrahydro-6-methoxy-8,8-dimethyl-1-phenylfuro[2,3-h]isoquinolinehydrochloride

[3513] Phosphorus oxychloride (3.4 mL, 36 mmol) was added to asuspension ofN-[2-(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)ethyl]benzamide(2.93 g, 9.00 mmol) in xylene (30 mL) and the mixture was heated underreflux for 5 hours, and then stirred at room temperature for 15 hours.The reaction mixture was cooled with ice, combined with 5 M solution ofsodium hydroxide (35 mL) and poured into ice water (100 mL). The aqueouslayer was extracted twice with diethyl ether, and the combined organiclayer was extracted twice with 2 M hydrochloric acid. The combinedaqueous layer was neutralized with 5 M aqueous solution of sodiumhydroxide, and extracted three times with diethyl ether. The combinedorganic layer was washed with a brine, dried over sodium sulfate,filtered, and concentrated under reduced pressure. The residue wassubjected to a column chromatography on a silica gel (hexane/ethylacetate 2:1 followed by 1:2) to obtain a free base of the titlecompound. This was dissolved in ethyl acetate (15 mL), combined with 4 Mhydrogen chloride/ethyl acetate solution (3 mL), and the precipitatedsolid was recovered by filtration and washed with diethyl ether toobtain the title compound (2.10 g, Yield: 68%).

[3514] Melting point: 213-215° C.

[3515]¹H NMR (CDCl₃) δ1.36 (6H, s), 2.35 (2H, s), 3.08 (2H, t, J=7.3Hz), 3.96-4.08 (2H, m), 4.02 (3H, s), 6.82 (1H, s), 7.54-7.77 (5H, m),14.50-14.80 (1H, br).

Example 436

[3516]3,4,8,9-Tetrahydro-6-methoxy-3,8,8-trimethyl-1-phenylfuro[2,3-h]isoquinoline

[3517] The title compound was obtained fromN-[2-(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-1-methylethyl]benzamideby the method similar to that in EXAMPLE 431. Yield: 71%.

[3518] Melting point: 133-134° C. (hexane-diisopropyl ether).

[3519]¹H NMR (CDCl₃) δ1.29 (3H, s), 1.35 (3H, s), 1.47 (3H, d, J=7.0Hz), 2.17-2.25 (2H, m), 2.44-2.73 (2H, m), 3.47-3.66 (1H, m), 3.92 (3H,s), 6.65 (1H, s), 7.40 (5H, s).

Example 437

[3520]3,4,8,9-Tetrahydro-6-methoxy-3,8,8-trimethyl-1-(4-pyridinyl)furo[2,3-h]isoquinoline

[3521] The title compound was obtained fromN-[2-(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-1-methylethyl]-4-pyridinecarboxamideby the method similar to that in EXAMPLE 431. Yield: 24%.

[3522] Melting point: 135-136° C. (hexane-diethyl ether).

[3523]¹H NMR (CDCl₃) δ1.30 (3H, s), 1.37 (3H, s), 1.47 (3H, d, J=6.8Hz), 2.19-2.37 (2H, m), 2.45-2.75 (2H, m), 3.51-3.66 (1H, m), 3.93 (3H,s), 6.67 (1H, s), 7.37 (2H, d, J=5.8 Hz), 8.68 (2H, d, J=5.8 Hz).

Example 438

[3524]3,4,8,9-Tetrahydro-6-methoxy-8,8-dimethyl-1-phenyl-3-furo[2,3-h]isoquinolinecarboxylicacid methyl ester

[3525] A mixture ofa-(benzoylamino)-2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranpropanoicacid methyl ester (2.81 g, 7.33 mmol) and phosphorus oxychloride (15 mL)was stirred at 100° C. for 2.5 hours. The reaction mixture wasconcentrated under reduced pressure, and the residue was combined withice and ethyl acetate. The resultant mixture was neutralized with conc.aqueous ammonia and the organic layer was separated, and the aqueouslayer was extracted with ethyl acetate. The combined organic layer waswashed twice with water, and then concentrated under reduced pressure.The residue was subjected to a column chromatography on a silica gel(hexane/ethyl acetate 2:1, 1:1 followed by 1:2) and crystallized fromethyl acetate-diisopropyl ether to obtain the title compound (1.41 g,Yield: 53%).

[3526] Melting point: 182-184° C.

[3527]¹H NMR (CDCl₃) δ1.29 (3H, s), 1.35 (3H, s), 2.20 (1H, d, J=16.3Hz), 2.31 (1H, d, J=16.3 Hz), 2.86-3.10 (2H, m), 3.82 (3H, s), 3.93 (3H,s), 4.24 (1H, dd, J=12.0, 6.6 Hz), 6.69 (1H, s), 7.35-7.51 (5H, m).

Example 439

[3528]N-[3′-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-yl]propanamide

[3529] The title compound was obtained from3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-amineand propionyl chloride by the method similar to that in EXAMPLE 30.Yield: 92%.

[3530] Melting point: 176-184° C. (ethyl acetate-diethyl ether).

[3531]¹H NMR (CDCl₃) δ1.20-1.32 (3H, m), 1.27 (6H, s), 1.29 (6H, s),2.26 (2H, s), 2.40 (2H, g, J=7.6 Hz), 2.71 (2H, s), 3.93 (3H, s), 6.63(1H, s), 7.26-7.68 (9H, m).

Example 440

[3532]N-[3′-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-yl]-2,2-dimethylpropanamide

[3533] The title compound was obtained from3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-amineand trimethylacetyl chloride by the method similar to that in EXAMPLE30. Yield: 68%.

[3534] Melting point: 189-193° C. (ethyl acetate-diethyl ether-hexane).

[3535]¹H NMR (CDCl₃) δ1.27 (6H, s), 1.30 (6H, s), 1.34 (9H, s), 2.26(2H, s), 2.71 (2H, s), 3.93 (3H, s), 6.63 (1H, s), 7.32-7.50 (3H, m),7.53-7.70 (6H, m).

Example 441

[3536]2,2,2-Trifluoro-N-[3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-yl]acetamide

[3537] A solution of3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-amine(192 mg, 0.450 mmol) and triethylamine (82 μL, 0.59 mmol) intetrahydrofuran (1 mL) was treated dropwise with trifluoroaceticanhydride (70 μL, 0.50 mmol) with cooling in ice, and stirred at thesame temperature for 10 minutes. The reaction mixture was combined withwater and a saturated aqueous solution of sodium hydrogen carbonate, andextracted twice with ethyl acetate. The combined organic layer waswashed with brine, dried through sodium sulfate, and concentrated. Theresidue was crystallized from ethyl acetate-hexane to obtain the titlecompound (222 mg, Yield: 94%).

[3538] Melting point: 149-154° C.

[3539]¹H NMR (CDCl₃) δ1.28 (6H, s), 1.32 (6H, br s), 2.02 (2H, s), 2.76(2H, s), 3.94 (3H, s), 6.65 (1H, s), 7.29-7.59 (8H, m), 8.95-9.20 (1H,m).

Example 442

[3540]N-[3′-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1-biphenyl]-4-yl]benzamide

[3541] The title compound was obtained from3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-amineand benzoyl chloride by the method similar to that in EXAMPLE 30.Quantitative.

[3542] Melting point: 204-207° C. (ethyl acetate-hexane). ¹H NMR (CDCl₃)δ1.27 (6H, s), 1.30 (6H, s), 2.27 (2H, s), 2.71 (2H, s), 3.93 (3H, s),6.63 (1H, s), 7.34-7.38 (1H, m), 7.42-7.64 (8H, m), 7.67-7.73 (2H, m),7.87-7.92 (2H, m), 7.94-8.07 (1H, m).

Example 443

[3543][3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-yl]carbamicacid methyl ester

[3544] A solution of sodium carbonate (72 mg, 0.68 mmol) in water (0.5mL) was added to a solution of3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-amine(192 mg, 0.450 mmol) in tetrahydrofuran (1 mL), and while cooling inice, methyl chloroformate (43 μL, 0.54 mmol) was added thereto, and themixture was stirred at the same temperature for 15 minutes. The reactionmixture was combined with water, and extracted twice with ethyl acetate.The combined organic layer was washed with water and brine, dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresidue was crystallized from ethyl acetate-diethyl ether to obtain thetitle compound (165 mg, Yield: 76%).

[3545] Melting point: 129-133° C.

[3546]¹H NMR (CDCl₃) δ1.27 (6H, s), 1.30 (6H, s), 2.26 (2H, s), 2.71(2H, s), 3.79 (3H, s), 3.93 (3H, s), 6.63 (1H, s), 6.69 (1H, br s), 7.34(1H, dt. J=7.7, 1.5 Hz), 7.39-7.49 (3H, m), 7.52-7.63 (4H, m).

Example 444

[3547]N-[3′-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-yl]formamide

[3548] Formic acid (0.5 ml) was treated dropwise with acetic anhydride(0.13 mL, 1.4 mmol) with cooling in ice, and the mixture was stirred atthe same temperature for 30 minutes.3′-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-amine(192 mg, 0.450 mmol) was added to the resultant solution and the mixturewas stirred at room temperature for 1.5 hours. To a suspension of sodiumhydrogen carbonate (1.85 g, 22.0 mmol) in water-ethyl acetate, thereaction mixture was added dropwise, and the mixture was extracted twicewith ethyl acetate. The combined organic layer was washed with water andbrine, dried over sodium sulfate, filtered and concentrated-underreduced pressure. The residue was crystallized from ethyl acetate toobtain the title compound (196 mg, Yield: 96%).

[3549] Melting point: 129-133° C.

[3550]¹H NMR (CDCl₃) δ1.24-1.32 (12H, m), 2.26 (2H, s), 2.73 (2H, s),3.93 (3H, s), 6.63 (1H, s), 7.05-7.17 (1H, m), 7.32-7.64 (8H, m), 8.36(0.6H, d, J=1.8 Hz), 8.72 (0.4H, d, J=11.2 Hz).

Example 445

[3551]2-(Acetylamino)-N-[3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-yl]acetamide

[3552] 1-Ethyl-3-(3-dimethylaminopropyl)carbodimide hydrochloride (100mg, 0.522 mmol) was added to a solution of3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-amine(171 mg, 0.401 mmol),

[3553] N-acetylglycine (52 mg, 0.44 mmol) and 1-hydroxy-1H-benzotriazole(68 mg, 0.44 mmol) in N,N-dimethylformamide (0.5 mL) and the mixture wasstirred at room temperature for 16 hours. The reaction mixture wascombined with water and a saturated aqueous solution of sodium hydrogencarbonate, and extracted twice with ethyl acetate. The combined organiclayer was washed with water and brine, dried over sodium sulfate,filtered and concentrated under reduced pressure. The residue wasrecrystallized from chloroform-diethyl ether to obtain the titlecompound (182 mg, Yield: 86%).

[3554] Melting point: 218-221° C.

[3555]¹H NMR (CDCl₃) δ1.28 (6H, s), 1.29 (6H, s), 2.10 (3H, s), 2.52(2H, s), 2.73 (2H, s), 3.93 (3H, s), 4.08 (2H, d, J=5.4 Hz), 6.45-6.55(1H, m), 6.63 (1H, s), 7.31-7.36 (1H, m), 7.43 (1H, t, J=7.7 Hz),7.49-7.60 (6H, m), 8.73-8.87 (1H, m).

Example 446

[3556]N-Methyl-N′-[3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-yl]urea

[3557] A solution of3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-amine(171 mg, 0.401 mmol) in chloroform (1 mL) was treated dropwise withmethyl isocyanate (26 μL, 0.44 mmol) and stirred at room temperature for3.5 hours. The reaction mixture was concentrated under reduced pressure,and the residue was subjected to a column chromatography on a basicsilica gel (ethyl acetate) to obtain the title compound (186 mg, Yield:96%).

[3558] Amorphous.

[3559]¹H NMR (CDCl₃) δ1.29 (12H, s), 2.25 (2H, s), 2.74 (2H, s), 2.77(3H, d, J=4.5 Hz), 3.93 (3H, s), 5.05 (1H, br s), 6.64 (1H, s), 6.98 (1Hbr s), 7.25-7.33-(3H, m), 7.38-7.45 (3H, m), 7.49-4.57 (2H, m).

Example 447

[3560]4-Oxo-4-[[3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-yl]amino]butyricacid

[3561] A solution of succinic anhydride (45 mg, 0.45 mmol) intetrahydrofuran (0.5 mL) was added to a solution of3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-amine(192 mg, 0.450 mmol) in tetrahydrofuran (1 mL) and the mixture wasstirred at 50° C. for 2.5 hours. The reaction mixture was concentratedunder reduced pressure, and the residue was subjected to a columnchromatography on a silica gel (chloroform followed bychloroform/methanol 5:1) to obtain the title compound (219 mg, Yield:92%).

[3562] Amorphous.

[3563]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.38 (6H, br s), 2.24 (2H, s), 2.46(4H, br s), 2.81 (2H, s), 3.94 (3H, s), 6.65 (1H, S), 7.25-7.60 (7H, m),7.61 (1H, s), 9.45-9.75 (1H, br).

Example 448

[3564]N-Methyl-N-[3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-yl]acetamide

[3565] The title compound was obtained fromN-[3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-yl]acetamideby the method similar to that in EXAMPLE 74. Yield: 79%

[3566] Amorphous.

[3567]¹H NMR (CDCl₃) δ1.27 (6H, s), 1.30 (6H, s), 1.92 (3H, s), 2.26(2H, s), 2.71 (2H, s), 3.29 (3H, s), 3.93 (3H, s), 6.63 (1H, s),7.20-7.30 (2H, m), 7.34 (1H, dt, J=7.6, 1.5 Hz), 7.48 (1H, t, J=7.6 Hz),7.58-7.69 (4H, m).

Example 449

[3568]3′-(6-Butoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2.3-h]isoquinolin-1-yl)[1,1′-blphenyl]-4-amine

[3569] To a solution of1-(3-bromophenyl)-6-butoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolnehydrochloride (493 mg, 1.00 mmol) in 1,2-dimethoxyethane (3 mL), ethanol(1.5 mL) and water (1.5 mL), sodium carbonate (265 mg, 2.50 mmol),4-(4.4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)aniline (263 mg, 1.20mmol) and tetrakis(triphenylphosphine)palladium (0) (24 mg, 0.021 mmol)were added, and the mixture was stirred at 80° C. for 14 hours. Thereaction mixture was combined with water, and washed twice with ethylacetate. The combined organic layer was washed with water, and extractedtwice with 0.5 M hydrochloric acid. The aqueous layer was neutralizedwith conc. aqueous ammonia, and extracted twice with ethyl acetate. Thecombined organic layer was washed with water and brine, dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresidue was subjected to a column chromatography on a basic silica gel(hexane/ethyl acetate, 3:1 followed by 2:1), and recrystallized fromethyl acetate-hexane to obtain the title compound (373 mg, Yield: 80%).

[3570] Melting point: 148-150° C.

[3571]¹H NMR (CDCl₃) δ0.98 (3H, t, J=7.3 Hz), 1.26 (6H, s), 1.28 (6H,s), 1.38-1.60 (2H, m), 1.74-1.91 (2H, m), 2.24 (2H, s), 2.68 (2H, s),3.72 (2H, br s), 4.10 (2H, t, J=6.9 Hz), 6.61 (1H, s), 6.74 (2H, d,J=8.4 Hz), 7.25-7.32 (1H, m), 7.35-7.47 (3H, m), 7.51-7.59 (2H, m).

Example 450

[3572]N-[3′-(6-Butoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-yl]acetamide

[3573] The title compound was obtained fromN-3′-(6-butoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyll-4-amineby the method similar to that in EXAMPLE 30. Yield: 95%.

[3574] Melting point: 202-204° C. (ethyl acetate-diethyl ether).

[3575]¹H NMR (CDCl₃) δ0.98 (3H, t, J=7.4 Hz), 1.28 (12H, s), 1.38-1.59(2H, m), 1.74-1.91 (2H, m), 2.15 (3H, s), 2.23 (2H, s), 2.70 (2H, s),4.11 (2H, t, J=6.8 Hz), 6.62 (1H, s), 7.29-7.60 (8H, m), 7.72 (1H, brs).

Example 451

[3576]4-Amino-3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-3-carboxylicacid methyl ester

[3577] A suspension of1-(3-bromophenyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinoline(1.66 g, 4.01 mmol),2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acidmethyl ester (1.22 g, 4.40 mmol), sodium carbonate (637 mg, 6.01 mmol)and tetrakis(triphenylphosphine)palladium (0) (93 mg, 0.080 mmol) in1,2-dimethoxyethane (12 mL), ethanol (6 mr) and water (6 mL) was stirredat 85° C. for 14 hours under nitrogen atmosphere. The reaction mixturewas combined with water, and extracted twice with ethyl acetate. Thecombined organic layer was washed with water and brine, dried oversodium sulfate-basic silica gel (eluting with ethyl acetate), andconcentrated under reduced pressure. The residue was subjected to acolumn chromatography on a basic silica gel (hexane/ethyl acetate, 3:1).The resultant material was dissolved in ethyl acetate, extracted twicewith 0.5 M hydrochloric acid, neutralized with conc. aqueous ammonia,and extracted twice with ethyl acetate. The combined organic layer waswashed twice with water, and concentrated under reduced pressure toobtain the title compound (1.85 g, yield: 95%).

[3578] Amorphous.

[3579]¹H NMR (CDCl₃) δ1.27 (6H, s), 1.31 (6H, s), 2.28 (2H, s), 2.71(2H, s), 3.89 (3H, s), 3.93 (3H, s), 5.79 (2H, br s), 6.63 (1H, s), 6.73(1H, d, J=8.4 Hz), 7.32 (1H, dt, J=7.3, 1.5 Hz), 7.38-7.47 (1H, m),7.51-7.59 (3H, m), 8.11 (1H, d, J=2.2 Hz).

Example 452

[3580]4-(Acetylamino)-3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-3-carboxylicacid methyl ester

[3581] A solution of4-amino-3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-3-carboxylicacid methyl ester (1.43 g, 2.95 mmol) in pyrldine (10 mL) was treateddropwise with acetic anhydride (0.28 mL, 3.0 mmol) with cooling in ice,and stirred at room temperature for 10 minutes and then at 60° C. for 1hour. The same volume of acetic anhydride was added to the mixture, andthe mixture was stirred at 100° C. for 2 hours. The reaction mixture wascombined with water and a saturated aqueous solution of sodium hydrogencarbonate, and extracted with ethyl acetate. The combined organic layerwas washed twice with water, and concentrated under reduced pressure.The residue was subjected to a column chromatography on a basic silicagel (hexane/ethyl acetate, 4:1 followed by 2:1), and recrystallized fromethyl acetate-hexane to obtain the title compound (1.12 g, yield: 72%).

[3582] Melting point: 116-119° C.

[3583]¹H NMR (CDCl₃) δ1.27 (6H, s), 1.31 (6H, s), 2.26 (3H, s), 2.27(2H, 's), 2.72 (2H, s), 3.93 (3H, s), 3.95 (3H, s), 6.63 (1H, s), 7.39(1H, dt, J=7.3, 1.6 Hz), 7.47 (1H, td, J=7.3, 1.2 Hz), 7.56-7.64 (2H,m), 7.79 (1H, dd, J=8.8, 2.4 Hz), 8.26 (1H, d, J=2.4 Hz), 8.78 (1H, d,J=8.8 Hz), 11.07 (1H, br s).

Example 453

[3584]4-(Acetylamino)-3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-3-carboxylicacid

[3585] b 5 M aqueous solution of sodium hydroxide (0.52 mL, 2.6 mmol)was added to a solution of4-(acetylamino)-3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-3-carboxylicacid methyl ester (692 mg, 1.32 mmol) in methanol (5 mL) and the mixturewas stirred at room temperature for 40 minutes and then heated underreflux for 10 minutes. The reaction mixture was concentrated underreduced pressure, combined with water (2 mL), and neutralized by adding2 M hydrochloric acid (1.3 mL, 2.6 mmol) dropwise, and the precipitatedpowder was recovered by filtration, washed with water and diethyl etherto obtain the title compound (671 mg, quantitative).

[3586] Melting point: 181-186° C.

[3587]¹H NMR (DMSO-d₆) δ1.20 (6H, s), 1.22 (6H, s), 2.14 (3H, s), 2.28(2H, s), 2.76 (2H, s) 3.85 (3H, s), 6.88 (1H, s), 7.38 (1H, d, J=7.6Hz), 7.55 (1H, t, J=7.6 Hz), 7.63 (1H, s), 7.81 (1H, d, J=7.6 Hz),7.84-7.93 (1H, m), 8.24 (1H, d J=2.2 Hz), 8.55 (1H, d, J=8.8 Hz), 11.75(1H, br s).

Example 454

[3588]N-[4′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-yl]acetamide

[3589] 4′-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)acetanilide (116mg, 0.444 mmol) and tetrakis(triphenylphosphine)palladium (0) (11 mg,0.0095 mmol) were added to a suspension of1-(4-bromophenyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolinehydrochloride (181 mg, 0.402 mmol) and sodium carbonate (149 mg, 1.41mmol) in 1,2-dimethoxyethane (1.2 mL), ethanol (0.6 mL) and water (0.6mL) and the mixture was stirred at 85° C. for 15 hours under nitrogenatmosphere. The reaction mixture was combined with water, and washedtwice with ethyl acetate The combined organic layer was washed withwater and brine, and dried through sodium sulfate-basic silica gel(eluting with ethyl acetate).and then concentrated under reducedpressure. The residue was subjected to a column chromatography on abasic silica gel (hexane/ethyl acetate, 2:1 followed by 1:1), andcrystallized from ethyl acetate-hexane to obtain the title compound (102mg, yield: 54%).

[3590] Melting point: 128-132° C.

[3591]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.33 (6H, s), 2.21 (3H, s), 2.32(2H, s), 2.70 (2H, s), 3.93 (3H, s), 6.62 (1H, s), 7.23 (1H, br s), 7.46(2H, d, J=8.6 Hz), 7.56-7.64 (4H, m), 7.60 (2H, d, J=8.6 Hz).

[3592] Example 455

[3593]N-[4′-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-3-yl]acetamide

[3594] The title compound was. obtained from 3-acetamidobenzeneboronicacid by the method similar to that in EXAMPLE 454. Yield: 84%.

[3595] Amorphous.

[3596]¹H NMR (CDCl₃) δ1.27 (6H, s), 1.33 (6H, s), 2.20 (3H, s), 2.31(2H, s), 2.71 (2H, s), 3.93 (3H, s), 6.63 (1H, s), 7.3-7.66 (8H, m),7.79 (1H, br s).

Example 456

[3597]3′-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-carboxylicacid ethyl ester

[3598] A suspension of1-(3-bromophenyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinoline(2.81 g, 6.78 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid ethyl ester(2.25 g, 8.15 mmol), sodium carbonate (1.08 g, 10.2 mmol) andtetrakis(trlphenylphosphine)palladium (0) (157 mg, 0.136 mmol) in1,2-dimethoxyethane (24 mL), ethanol (12 mL) and water (12 mL) wasstirred at 80° C. for 14 hours under nitrogen atmosphere. The reactionmixture was combined with water and extracted twice with ethyl acetate.The combined organic layer was washed with water and brine, driedthrough.sodium sulfate-basic silica gel (eluting with ethyl acetate),and concentrated under reduced pressure. The residue was subjected to acolumn chromatography on a basic silica gel (hexane/ethyl acetate, 10:1)to obtain the title compound (2.87g, yield: 88%).

[3599] Amorphous.

[3600]¹H NMR (CDCl₃) δ1.27 (6H, s), 1.30 (6H, s), 1.42 (3H, t, J=7.1Hz), 2.26 (2H, s), 2.72 (2H, s), 3.93 (3H, s), 4.40 (2H, q, J=7.1 Hz),6.63 (1H, s), 7.37-7.54 (2H, m), 7.62-7.71 (4H, m), 8.10 (2H, d, J=8.4Hz).

Example 457

[3601]3′-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-carboxylic acid

[3602] 1 M aqueous solution of sodium hydroxide (20 mL, 20 mmol) wasadded to -a solution of3-′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-carboxylicacid ethyl ester (2.74 g, 5.67 mmol) in ethanol (15 mL) and the mixturewas stirred at 70° C. for 30 minutes. The reaction mixture was cooledwith ice, combined with 1 M hydrochloric acid (20 mL, 20 mmol),saturated with sodium chloride, and then extracted three times withethyl acetate. The combined organic layer was dried over sodium sulfate,filtered and concentrated under reduced pressure. The residue wascrystallized from ethyl acetate-diethyl ether to obtain the titlecompound (2.26 g, yield: 87%).

[3603] Melting point: 161-165° C.

[3604]¹H NMR (DMSO-d₆) δ1.17 (6H, s), 1.19 (6H, s), 2.26 (2H, s), 2.67(2H, s), 3.82 (3H, s), 6.84 (1H, s), 7.40 (1H, d, J=7.7 Hz), 7.56 (1H,t, J=7.7 Hz), 7.67 (1H, s), 7.79-7.87 (3H, m), 8.03 (2H, d, J=8.4 Hz).

Example 458

[3605]3′-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoqulnolin-1-yl)[1,1′-biphenyl]-4-carboxamide

[3606] 1-ethyl-3-(3-dimethylaminopropyl)carbodiumide hydrochloride (200mg, 1.04 mmol) was added to a suspension of3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-carboxylicacid (365 mg, 0.801 mmol) and 1-hydroxy-1H-benzotriazole ammonium salt(147 mg, 0.966 mmol) in N,N-dimethylformamide (1.5 mL) and the mixturewas stirred at-room temperature for 15 hours. The reaction mixture wascombined with water and saturated aqueous solution of sodium hydrogencarbonate, and extracted twice with ethyl acetate. The combined organiclayer was washed with ater and a brine, dried over sodium sulfate,filtered and concentrated under reduced pressure. The residue wascrystallized from ethyl acetate-hexane to obtain the title compound (286mg, yield: 79%).

[3607] Melting point: 134-137° C. (decomposition).

[3608]¹H NMR (CDCl₃) δ1.27 (6H, s), 1.30 (6H, s), 2.25 (2H, s), 2.72(2H, s), 3.93 (3H, s), 5.50-6.40 (2H, m), 6.63 (1H, s), 7.39-7.54 (2H,m), 7.61-7.63 (2H, m), 7.69 (2H, d, J=8.5 Hz), 7.88 (2H, d, J=8.5 Hz).

Example 459

[3609]N-Methyl-3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-carboxamide

[3610] 1-Ethyl-3-(3-dimethylaminopropyl)carbodlimide hydrochloride (200mg, 1.04 mmol) was added to a suspension of3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoguinolin-1-yl)[1,1′-biphenyl]-4-carboxylicacid (365 mg, 0.801 mmol), 40% methylamine/methanol solution (75 mg,0.97 mmol) and 1-hydroxy-1H-benzotriazole (135 mg, 0.880 mmol) inN,N-dimethylformamide (1.5 mL) and the mixture was stirred at roomtemperature for 20 hours. The reaction mixture was combined with waterand a saturated aqueous solution of sodium hydrogen carbonate, andextracted twice with ethyl acetate. The combined organic layer waswashed with water and brine, dried through sodium sulfate-basic silicagel (eluting with ethyl acetate), and concentrated under reducedpressure. The residue was crystallized from ethyl acetate-hexane toobtain the title compound (317 mg, yield: 84%).

[3611] Melting point: 242-244° C.

[3612]¹H NMR (CDCl₃) δ1.27 (6H, s), 1.30 (6H, s), 2.25 (2H, s), 2.72(2H, s), 3.04 (3H, d, J=4.8 Hz), 3.93 (3H, s), 6.15-6.30 (1H, m), 6.63(1H, s), 7.37-7.53 (2H, m), 7.59-7.70 (2H, m), 7.66 (2H, d, J=8.4 Hz),7.82 (2H, d, J=8.4 Hz).

Example 460

[3613]N,N′-Dimethyl-3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-carboxamide

[3614] 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (200mg, 1.04 mmol) was added to a suspension of3′(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-carboxylicacid (365 mg, 0.801 mmol), 2 M dimethylamine/tetrahydrofuran solution(0.48 mL, 0.96 mmol) and 1-hydroxy-1H-benzotriazole (135 mg, 0.880 mmol)in N,N-dimethylformamide (1.5 mL) and the mixture was stirred at roomtemperature for 17 hours. The reaction mixture was combined with waterand a saturated aqueous solution of sodium hydrogen carbonate, andextracted twice with ethyl acetate. The combined organic layer waswashed with water and brine, dried through sodium sulfate-basic silicagel (eluting with ethyl acetate), concentrated under reduced pressure toobtain the title compound (319 mg, yield: 83%).

[3615] Amorphous.

[3616]¹H NMR (CDCl₃) δ1.27 (6H, s), 1.30 (6H, s), 2.25 (2H, s), 2.71(2H, s), 3.03 (3H, br s), 3.12 (3H, br s), 3.93 (3H, s), 6.63 (1H, s),7.36-7.53 (4H, m), 7.58-7.68 (4H, m).

Example 461

[3617]N-[3′-(3,4,8,9-Tetrahydro-6-hydroxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)(1,1′-biphenyl]-4-yl]acetamide

[3618] A suspension of1-(3-bromophenyl)-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolinol(1.40 g, 3.50 mmol),4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acetanilide (1.01 g,3.87 mmol), sodium carbonate (927 mg, 8.75 mmol) andtetrakis(triphenylphosphine)palladium (0) (81 mg, 0.070 mmol) in1,2-dimethoxyethane (10 mL), ethanol (5 mL) and water (5 mL) was stirredat 80° C. for 14 hours under nitrogen atmosphere. The reaction mixturewas combined with water, and extracted twice with ethyl acetate. Thecombined organic layer was washed with brine, dried through sodiumsulfate-basic silica gel (eluting with ethyl acetate followed by ethylacetate/methanol, 10:1) and concentrated under reduced pressure, and theprecipitated powder was recovered by filtration, washed with ethylacetate-diethyl ether mixture to obtain the title compound (921 mg,yield: 58%).

[3619] Melting point: 185-189° C.

[3620]¹H NMR (DMSO-d₆) δ1.14 (6H, s), 1.19 (6H, s), 2.06 (3H, s), 2.23(2H, s), 2.56 (2H, s), 6.56 (1H, s), 7.29 (1H, d, J=7.6 Hz), 7.42-7.77(7H, m), 10.05 (1H, s).

Example 462

[3621]1-[4′-(Acetylamino)[1,1′-biphenyl]-3-yl]-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-6-yltrifluoromethanesulfonate

[3622] The title compound was obtained fromN-[3′-(3,4,8,9-tetrahydro-6-hydroxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-yl]acetamideby the method similar to that in EXAMPLE 95. Yield: 96%.

[3623] Amorphous.

[3624]¹H NMR (CDCl₃) δ1.28 (6H, s), 1.29 (6H, s), 2.13-2.23 (3H, m),2.30 (2H, s), 2.72 (2H, s), 6.95 (1H, s), 7.29-7.70 (9H, m).

Example 463

[3625]N-[3′-(3,4,8,9-Tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-yl]acetamide

[3626] Formic acid (64 μL, 1.7 mmol) was added to a solution of1-[4′-(acetylamino)[1,1′-blphenyl]-3-yl]-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-6-yltrifluoromethanesulfonate (496 mg, 0.846 mmol), triethylamine (0.35 mL,2.5 mmol), palladium (II) acetate (4.7 mg, 0.021 mmol) andtriphenylphosphine (11 mg, 0.042 mmol) in N,N-dimethylformamide (1.5 mL)and the mixture was stirred at 60° C. for 4 hours under nitrogenatmosphere. The reaction mixture was combined with water and a saturatedaqueous solution of sodium hydrogen carbonate, and extracted twice withethyl acetate. The combined organic layer was washed with water andbrine, dried through sodium sulfate-basic silica gel (eluting with ethylacetate), and concentrated under reduced pressure. The residue wassubjected to a column chromatography on a basic silica gel (hexane/ethylacetate, 2:1 followed by 1:1), crystallized from ethyl acetate-hexane toobtain the title compound (294 mg, yield: 79%).

[3627] Melting point: 198-200° C.

[3628]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.28 (6H, s), 2.16 (3H, s), 2.24(2H, s), 2.72 (2H, s), 6.76 (1H, d, J=7.8 Hz), 6.99 (1H, d, J=7.8 Hz),735 (1H, dt, J=7.4, 1.4 Hz), 7.44 (1H, td, J=7.4, 1.0 Hz), 7.49-7.62(7H, m).

Example 464

[3629]1-(3-Bromophenyl)-3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-6-furo[2,3-h]isoquinolin-6-yltrifluoromethanesulfonate

[3630] The title compound was obtained from1-(3-bromophenyl)-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolinolby the method similar to that in EXAMPLE 95. Quantitative.

[3631] A gum.

[3632]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.34 (6H, s), 2.29 (2H, s), 2.69(2H, s), 6.95 (1H, s), 7.14-7.38 (2H, m), 7.53-7.60 (2H, m).

Example 465

[3633]3′-(3,4,8,9-Tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-amine

[3634] Formic acid (0.73 mL, 19 mmol) was added to a solution of1-(3-bromophenyl)-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-6-yltrifluoromethanesulfonate (5.13 g, 9.64 mmol), triethylamine (4.0 mL, 29mmol), palladium (II) acetate (54 mg, 0.24 mmol) and triphenylphosphine(126 mg, 0.480 mmol) in N,N-dimethylformamide (20 mL) and the mixturewas stirred at 65° C. for 2 hours under nitrogen atmosphere. Thereaction mixture was combined with water and saturated aqueous solutionof sodium hydrogen carbonate, and extracted twice with ethyl acetate.The combined organic layer was washed with water and brine, driedthrough sodium sulfate-basic silica gel (eluting with ethyl acetate),and concentrated under reduced pressure. The residue was subjected to acolumn chromatography on a silica gel (hexane/ethyl acetate, 10:1) toobtain an oil containing1-(3-bromophenyl)-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinoline.

[3635] This material,4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.21 g, 5.52mmol), sodium carbonate (795 mg, 7.50 mmol) andtetrakis(triphenylphosphine)palladium (0) (116 mg, 0.100 mol) weresuspended in 1,2-dimethoxyethane (15 mL), ethanol (7 mL) and water (7mL), and the mixture was stirred at 80° C. for 15hours under nitrogenatmosphere. The reaction mixture was combined with water and extractedtwice with ethyl acetate. The combined organic layer was washed withwater and brine, dried through sodium sulfate-basic silica gel (elutingwith ethyl acetate), and concentrated under reduced pressure. Theresidue was subjected to a column chromatography on a basic silica gel(hexane/ethyl acetate, 10:1 followed by 2:1), and crystallized fromethyl acetate-hexane to obtain the title compound (1.35g, yield: 35%).

[3636] Melting point: 161-163° C.

[3637]¹H NMR (CDCl₃) δ1.25 (12H, s), 2.24 (2H, s), 2.70 (2H, s), 3.73(2H, br s), 6.74 (2H, d, J=8.4 Hz), 6.75 (1H, d, J=8.0 Hz), 6.98 (1H, d,J=8.0 Hz), 7.27-7.34 (1H, m), 7.36-7.48 (3H, m), 7.54-7.60 (2H, m).

Example 466

[3638]2,2,2-Trifluoro-N-[3′-(3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-yl]acetamide

[3639] The title compound was obtained from3′-(3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-amineby the method similar to that in EXAMPLE 441. Yield: 83%.

[3640] Melting point: 228-230° C. (ethyl acetate-hexane).

[3641]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.30 (6H, s), 2.19 (2H, s), 2.75(2H, s), 6.78 (1H, d, J=7.9 Hz), 7.01 (1H, d, J=7.9 Hz), 7.31-7.62 (8H,m), 8.82 (1H, br s).

Example 467

[3642]4-[[[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoqulnolin-1-yl)phenyl]amino]carbonyl]benzoicacid methyl ester

[3643] Terephthaloyl monomethyl chloride (1.91 g, 9.62 mmol) was addedto a solution of3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine(2.81 g, 8.02 mmol) and triethylamine (1.5 mL, 11 mmol) intetrahydrofuran (15 mL) with cooling in ice, and the mixture was stirredat room temperature for 10 minutes. The reaction mixture was combinedwith water, and extracted twice with ethyl acetate. The. combinedorganic layer was washed with a saturated aqueous solution of sodiumhydrogen carbonate, water and brine, dried through sodium sulfate-basicsilica gel (elutlng with ethyl acetate), and concentrated under reducedpressure. The residue was subjected to a column chromatography on abasic silica gel (hexane/ethyl acetate, 2:1 followed by 1:1), andrecrystallized from ethyl acetate-hexane to obtain the title compound(3.75 g, yield: 91%).

[3644] Melting point: 156-160° C.

[3645]¹H NMR (CDCl₃) δ1.16 (6H, br s), 1.33 (6H, s), 2.34 (2H, s), 2.60(2H, br s), 3.92 (3H, s), 3.96 (3H, s), 6.59 (1H, s), 7.13 (1H, d, J=7.7Hz), 7.37 (1H, t, J=7.7 Hz), 7.56 (1H, t, J=1.8 Hz), 7.89-7.98 (3H, m),8.12 (2H, d, J=7.8 Hz), 8.66 (1H, br s).

Example 468

[3646]4-[[[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]amino]carbonyl]benzoicacid hydrochloride

[3647] 5 M aqueous solution of sodium hydroxide (0.50 mL, 2.5 mmol) wasadded to a solution of4-[[[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]amino]carbonyl]benzoicacid methyl ester (1.03 g, 2.01 mmol) in methanol (10 mL) and themixture was stirred at room temperature for 1.5 hours and then heatedunder reflux for 1.5 hours. The reaction mixture was concentrated underreduced pressure, and treated dropwise with 1 M hydrochloric acid (5.0mL, 5.0 mmol) with cooling in ice. Brine was added to the mixture, andthe mixture was extracted twice with ethyl acetate-tetrahydrofuranmixture. The combined organic layer was dried over sodium sulfate,filtered and concentrated under reduced pressure to obtain thetitle.compound (1.06 g, yield: 99%).

[3648] Amorphous.

[3649]¹H NMR (CDCl₃) δ1.34 (6H, s), 1.62 (3H, br s), 1.73 (3H, br s),2.26-2.54 (2H, m), 2.94-3.24 (2H, m), 3.98 (3H, s), 6.72 (1H, 8), 7.24(1H, d, J=3 8.1 Hz), 7.47 (1H, t, J=8.1 Hz), 7.83 (2H, d, J=8.6 Hz),7.90 (2H, d, J=8.6 Hz), 8.25 (1H, s), 8.35 (1H, d, J=8.1 Hz), 10.01 (1H,br s), 12.88 (1H, br s).

Example 469

[3650]N-Methyl-N′-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-1,4-benzenedicarboxamide

[3651] Triethylamine (0.17 mL, 1.2 mol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (125 mg,0.652 mmol) were added to a solution of4-[[[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]amino]carbonyl]benzoicacid hydrochloride (268 mg, 0.501 mmol), 40% methylamine/methanolsolution (55 mg, 0.56 mmol) and 1-hydroxy-1H-benzotriazole (85 mg, 0.56mmol) in N,N-dimethylformamide (1 mL) and the mixture was stirred atroom temperature for 24 hours. The reaction mixture was combined withwater, and extracted twice with chlorofonm-methanol mixture. Thecombined organic phase was washed with brine, dried through sodiumsulfate-basic silica gel (eluting with ethyl acetate/methanol, 10:1) andconcentrated under reduced pressure. The residue was recrystallized fromchloroform-methanol-diethyl ether to obtain the title compound (215 mg,Yield: 84%).

[3652] Melting point: 310-312° C.

[3653]¹H NMR (DMSO-d₄) δ1.15 (6H, s), 1.23 (6H, s), 2.33 (2H, br s),2.64 (2H, s), 2.81 (3H, d, J=4.5 Hz), 3.82 (3H, s), 6.82 (1H, s),7.08-7.12 (1H, m), 7.40 (1H, t, J=8.0 Hz), 7.77-7.81 (1H, m), 7.88-7.94(1H, m), 7.95 (2H, d, J=8.3 Hz), 8.04 (2H, d, J=8.3 Hz), 8.57-8.63 (1H,m), 10.40 (1H, s).

Example 470

[3654]2-[(3,4,8,9-Tetrahydro-6-methoxy-3,8,8-trimethyl-1-phenylfuro[2,3-h]isoquinolin-3-yl)methyl]-1H-isoindole-1,3(2H)-dione

[3655] A suspension of3-(bromomethyl)-3,4,8,9-tetrahydro-6-methoxy-3.8,8-trimethyl-1-phenylfuro[2,3-h]isoquinoline(2.49 g, 6.01 mmol), potassium phthalimide (90%) (1.86 g, 9.0 mmol) inN,N-dimethylacetamide (25 mL) was heated under reflux for 2.5 hoursunder nitrogen atmosphere The reaction mixture was combined with water,and extracted twice with ethyl acetate. The combined organic layer waswashed twice with water, and concentrated under reduced pressure. Theresidue was subjected to a column chromatography on a silica gel(hexane/ethyl acetate, 2:1), crystallized from ethyl acetate-hexane, andrecrystallized from methanol-acetone-hexane to obtain the title compound(1.56 g, yield; 54%).

[3656] Melting point: 121-125° C.

[3657]¹H NMR (CDCl₃) δ1.19 (3H, s), 1.22 (3H, s), 1.38 (3H, s),1.97-2.19 (2H, m), 2.81 (1H, d, J=15.9 Hz), 3.02 (1H, d, J=15.9 Hz),3.85 (1H, d, J=13.6 Hz), 3.86 (3H, s), 3.96 (1H, d, J=13.6 Hz), 6.54(1H, s), 7.36-7.52 (5H, m), 7.61-7.80 (4H, m).

Example 471

[3658]3,4,8,9-Tetrahydro-6-methoxy-3,8,8-trimethyl-1-phenyl-3-furo[2,3-h]isoquinolinemethanamine

[3659] Hydrazine monohydrate (0.25 mL, 5.2 maol) was added to asuspension of2-[(3,4,8,9-tetrahydro-6-methoxy-3,8,8-trimethyl-1-phenylfuro[2,3-h]isoquinolin-3-yl)methyl]-1H-isoindole-1,3(2H)-dione(2.08 g, 4.33 mmol) in ethanol (20 mL) and heated under reflux for 4hours with adding the same amount of the hydrazine monohydrate after 2hours and after 3 hours. The reaction mixture was combined with 1 Maqueous solution of sodium hydroxide (9.0 mL, 9.0 mmol), diluted withwater, and extracted twice with ethyl acetate. The combined organiclayer was washed twice with water, and concentrated under reducedpressure. The residue was subjected to a column chromatography on abasic silica gel (ethyl acetate/methanol, 100:1), and recrystallizedfrom ethyl acetate-hexane to obtain the title compound (823 mg. Yield:54%).

[3660] Melting point: 143-145° C.

[3661]¹H NMR (CDCl₃) δ1.06 (3H, s), 1.29 (3H, s), 1.33 (3H, s), 2.16(1H, d, J=16.5 Hz), 2.25 (1H, d, J=16.5 Hz), 2.49 (1H, d, J=15.4 Hz),2.80 (1H, d, J=12.6 Hz), 2.89 (1H, d, J=12.6 Hz), 2.93 (1H, d, J=15.4Hz), 3.92 (3H, s). 6.63 (1H, s), 7.39 (5H, s).

Example 472

[3662](3,4,8,9-Tetrahydro-6-methoxy-8,8-dimethyl-1-phenylfuro[2,3-h]isoquinolin-3-yl)methylacetate

[3663] Phosphorus oxychloride (9.4 mL 0.10 mol) was added to asuspension of2-(benzoylamino)-3-(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)propylacetate (3.34 g, 8.40 mmol) in acetonitrile (65 mL) and heated underreflux for 1.5 hours. Water was poured into the reaction mixture, whichwas neutralized with conc. aqueous ammonia with cooling in ice andextracted twice with ethyl acetate. The combined organic layer waswashed twice with water, and concentrated under reduced pressure. Theresidue was recrystallized from ethyl acetate-hexane to obtain the titlecompound (2.62 g, yield: 82%).

[3664] Melting point: 168-169° C.

[3665]¹H NMR (CDCl₃) δ1.28 (3H, s), 1.36 (3H, s), 2.12 (3H, s), 2.19(1H, d, J=8.1 Hz), 2.31 (1H, d, J=8.1 Hz), 2.52-2.79 (2H, m), 3.54-3.76(1H, m), 3.93 (3H, s), 4.34 (1H, dd, J=11.0, 6.6 Hz), 4.54 (1H, dd,J=11.0, 6.2 Hz), 6.68 (1H, s), 7.42 (5H, s).

Example 473

[3666]3,4,8,9-Tetrahydro-6-methoxy-8,8-dimethyl-1-phenyl-3-furo[2,3-h]isoquinolinemethanol

[3667] 5 M aqueous solution of sodium hydroxide (1.6 mL, 8.0 mmol) wasadded to a solution of(3,4,8,9-tetrahydro-6-methoxy-8,8-dimethyl-1-phenylfuro[2,3-h]isoquinolin-3-yl)methylacetate (1.00 g, 2.64 mmol) in methanol (5 mL) and tetrahydrofuran (5mL), and the mixture was stirred at room temperature for 10 minutes. Thereaction mixture was combined with water, and extracted twice with ethylacetate. The combined organic layer was washed twice with water, andconcentrated under reduced pressure. The residue was recrystallized fromethyl acetate-diisopropyl ether to obtain the title compound (553 mg,yield: 62%).

[3668] Melting point: 156-158° C.

[3669]¹H NMR (CDCl₃) δ1.28 (3H, s), 1.38 (3H, s), 2.21 (1H, d, J=8.1Hz), 2.35 (1H, d, J=8.1 Hz), 2.51-2.70 (2H, m), 2.90-3.15 (1H, br),3.36-3.57 (1H, m), 3.76 (1H, dd, J=10.7, 7.7 Hz), 3.87-4.03 (1H, m),3.93 (3H, s), 6.68 (1H, s), 7.43 (5H, s).

Example 474

[3670]2-[(3,4,8,9-Tetrahydro-6-methoxy-8,8-dimethyl-1-phenylfuro[2,3-h]isoquinolin-3-yl)methyl]-1H-isoindole-1,3(2H)-dione

[3671] A solution of3,4,8,9-tetrahydro-6-methoxy-8,8-dimethyl-1-phenyl-3-furo[2,3-h]isoquinolinemethanol(793 mg, 2.35 mmol) in pyridine (10 mL) was cooled with ice, treateddropwise with methanesulfonyl chloride (0.22 mL, 2.8 mmol), stirred atthe same temperature for 30 minutes, treated further withmethanesulfonyl chloride (0.04 mL, 0.05 mmol), and stirred further for30 minutes. The reaction mixture was combined with water and a saturatedaqueous solution of sodium hydrogen carbonate, and extracted twice withethyl acetate. The combined organic layer was washed twice with waterand concentrated under reduced pressure. The residue was combined withtoluene, and concentrated under reduced pressure again to obtain(3,4,8,9-tetrahydro-6-methoxy-8,8-dimethyl-1-phenylfuro[2,3-h]isoquinolin-3-yl)methylmethanesulfonate.

[3672] This was dissolved in N,N-dimethylformamlde, potassiumphthalimide (90%, 725 mg, 3.5 mmol) was added thereto, and the mixturewas stirred at 100° C. for 4.5 hours. The reaction mixture was combinedwith water, and extracted twice with ethyl acetate. The combined organiclayer was washed twice with water, and concentrated under reducedpressure. The residue was crystallized from ethyl acetate-dulsopropylether to obtain the title compound (337 mg, yield: 31%).

[3673] Melting point: 228-229° C.

[3674]¹H NMR (CDCl₃) δ1.26 (3H, s), 1.34 (3H, s), 2.18 (1H, d, J=16.5Hz), 2.32 (1H, d, J=16.5 Hz), 2.57-2.75 (2H, m), 3.78-4.15 (2H, m), 3.87(3H, s), 4.24 (1H, dd, J=13.2, 5.4 Hz), 6.61 (1H, s), 7.34-7.48 (5H, m),7.68-7.92 (4H, m).

Example 475

[3675]3,4,8,9-Tetrahydro-6-methoxy-8,8-dimiethyl-1-phenyl-3-furo[2,3-h]isoquinolinemethanaminedithydrochloride

[3676] Hydrazine monohydrate (84 μL, 1.7 mmol) was added to a suspensionof2-[(3,4,8,9-tetrahydro-6-methoxy-8,8-dimethyl-1-phenylfuro[2,3-h]isoquinolin-3-yl)methyl]-1H-isoindole-1,3(2H)-dione(350 mg, 0.750 mmol) in ethanol (4 mL) and the mixture was heated underreflux for 2.5 hours. The reaction mixture was combined with 1 M aqueoussolution of sodium hydroxide, diluted with water, and extracted twicewith ethyl acetate. The combined organic layer was washed twice withwater, and concentrated under reduced pressure. The residue wassubjected to a column chromatography on a basic ssilica gel (ethylacetate followed by ethyl acetate/methanol, 10:1) to obtain3,4,8,9-tetrahydro-6-methoxy-8,8-dimethyl-1-phenyl-3-furo[2,3-h]isoqulnolinemethanamine(164 mg) as an amorphous material. This was dissolved in ethyl acetate(2 mL), combined with 0.8 M hydrogen chloride/methanol solution (1.8 mL,1.4 mmol) and concentrated under reduced pressure. The residue wascrystallized from ethanol-ethyl acetate to obtain the title compound(140 mg, yield: 46W).

[3677] Melting point: 192-194° C.

[3678]¹H NMR (DMSO-d₆) δ1.22 (3H, s), 1.26 (3H, a), 2.26 (2H, s),3.05-3.40 (4H, m), 3.80-4.50 (1H, m), 3.94 (3H, s), 7.10 (1H, s),7.55-7.78 (5H, m), 8.35-8.65 (3H, m).

Example 476

[3679]N-[3′-(3,4,8,9-Tetrahydro-6-methoxy-3,3.8,8-tetramethyl-2-oxidofuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-3-yl]acetamide

[3680] The title compound was obtained fromN-[3′-(1,2,3,4,8,9-hexahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1.1′-biphenyl]-3-yl]acetamideby the method similar to that in EXAMPLE 110. Yield: 66%.

[3681] Melting point: 158-162° C. (methanol-diethyl ether).

[3682]¹H NMR (CDCl₃) δ1.24 (3H, s), 1.28 (3H, s), 1.51 (6H, s), 2.04(2H, s), 2.13 (3H, s), 3.09 (2H, s), 3.9 (3H s), 6.65 (1H, s), 7.27-7.53(5H, m), 7.56-7.69 (3H, m), 7.69 (1H, br s).

Example 477

[3683]N-(3,5-Dichloro-1-oxido-4-pyridinyl)-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide

[3684] Conc. sulfuric acid (0.393 mL, 7.38 mmol) was added to a mixtureof 3-cyano-N-(3,5-dichloro-1-oxido-4-pyridinyl)benzamide (0.84 g, 2.84mmol),1-(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-2-methyl-1-propanol(1.07 g, 4.26 mmol), acetic acid (7 mL) and toluene (10 mL) and themixture was stirred at 80° C. for 1 hour. The reaction solution wascooled with ice, combined with water and washed with diethyl ether. Theaqueous layer was made basic with aqueous ammonia and 1 M aqueoussolution of sodium hydroxide, and washed with dulsopropyl ether-diethylether (1:1). The aqueous layer was adjusted at pH 7 with 2 Mhydrochloric acid, and extracted with ethyl acetate. The extract waswashed with brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was subjected to acolumn chromatography on a silica gel (ethyl acetate followed by ethylacetate/methanol, 23:2), and then crystallized from ethyl acetate toobtain the title compound (0.20 g, yield: 13%).

[3685] Melting point: 264-266° C.

[3686]¹H NMR (DMSO-d₆) δ1.17 (6H, s), 1.22 (6H, s), 2.23 (2H, s), 2.67(2H, s), 3.82 (3H, s), 6.84 (1H, s), 7.57-7.68 (2H, m), 8.01-8.09 (2H,m), 8.72 (2H, s), 10.58 (1H, br s).

Example 47

[3687]N-(2-Oxo-3-piperidinyl)-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide

[3688] The title compound was obtained from3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid hydrochloride and 3-amino-3,4,5,6-tetrahydro-2(1H)-pyridinone bythe method similar to that in EXAMPLE 159. Yield: 63%

[3689] Amorphous.

[3690]¹H NMR (CDCl₃) δ1.23 (3H, s), 1.28 (3H, s), 1.30 (6H, s),1.58-1.80 (2H, m), 1.88-1.98 (2H, m), 2.18 (2H, s), 2.59-2.72 (3H, m),3.27-3.38 (2H, m), 3.92 (3H, s), 4.40-4.50 (1H, m), 6.27 (1H, br s),6.62 (1H, s), 7.33-7.36 (1H, m), 7.43-7.48 (1H, m), 7.88-7.95 (2H, m).

Example 479

[3691](S)-N-[Hexahydro-2-oxo-1H-azepin-3-yl]-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide

[3692] The title compound was obtained from3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid hydrochloride and (S)-3-aminohexahydro-2H-azepin-2-one by themethod similar to that in EXAMPLE 159.

[3693] Yield: 65%.

[3694] Amorphous.

[3695] [a]D+23.1° (c 1.0, methanol)

[3696]¹H NMR (CDCl₃) δ1.23 (3H, s), 1.30 (9H, s), 1.51-2.05 (6H, m),2.16 (2H, s), 2.70 (2H, s), 3.20-3.38 (2H, m), 3.92 (3H, s), 4.68-4.78(1H, m), 6.53 (1H, br s), 6.62 (1H, s), 7.42-7.51 (2H, m), 7.69-7.73(1H, m), 7.88-7.92 (2H, m).

Example 480

[3697](R)-N-[Hexahydro-2-oxo-1H-azepin-3-yl]-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide

[3698] The title compound was obtained from3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid hydrochloride and (R)-3-aminohexahydro-2H-azepin-2-one by themethod similar to that in EXAMPLE 159.

[3699] Yield: 33%.

[3700] Amorphous.

[3701] [a]D−22.5° (c 1.0, methanol).

[3702]¹H NMR (CDCl₃) δ1.23 (3H, s), 1.30 (9H, s), 1.51-2.25 (6H, m),2.17 (2H, s), 2.70 (2H, s), 3.20-3.36 (2H, m), 3.92 (3H, s), 4.69-4.78(1H, m), 6.29 (1H, br s), 6.62 (1H, s), 7.41-7.51 (2H, m), 7.69-7.73(1H, m), 7.88-7.91 (2H, m).

Example 481

[3703]3-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid methyi ester

[3704] Conc. sulfuric acid (7.86 mL, 0.147 mol) was added to a mixtureof1-(7-ethoxy-2,3-dihydro-2,2-dimethyl-5-benzofuranyl)-2-methyl-1-propanol(15.0 g, 56.7 mmol), methyl 3-cyanobenzoate (9.14 g, 56.7 mmol), aceticacid (80 mL) and toluene (100 mL) and the mixture was stirred at 80° C.for 1 hour. The reaction mixture was cooled with ice and combined withwater, and washed with diethyl ether. The aqueous layer was cooled withice, made basic with conc. aqueous ammonium, and extracted with ethylacetate. The extract was washed with water, and concentrated underreduced pressure. The residue was subjected to a column chromatographyon a basic silica gel (hexane/ethyl acetate, 4:1) to obtain the titlecompound (9.00 g, yield: 39%).

[3705] Amorphous.

[3706]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.29 (6H, s), 1.47 (3H, t, J=7.0Hz), 2.15 (2H, s), 2.68 (2H, s), 3.92 (3H, s), 4.18 (2H, q, J=7.0 Hz),6.62 (1H, s), 7.47 (1H, t, J=8.0 Hz), 7.61 (1H, d, J=8.0 Hz), 8.05-8.08(2H, m).

[3707] Example 482

[3708]3-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid hydrochloride

[3709] 5 M aqueous solution of sodium hydroxide (12 mL) was added to asolution of3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid methyl ester (8.80 g, 21.6 mmol) in methanol (40 mL) and themixture was stirred at 50° C. for 12 hours. The reaction mixture wascooled with ice, combined with 5 M hydrochloric acid(17 mL), andconcentrated under reduced pressure. The residue was combined withethanol, filtered, and the filtrate was concentrated under reducedpressure repetitively for three times. The residue was crystallized fromethyl acetate to obtain the title compound (6.15 g, yield: 66%).

[3710] Melting point: 240-243° C.

[3711]¹H NMR (DMSO-d₆) δ1.22 (6H, s), 1.37 (3H, t, J=7.0 Hz), 1.46 (6H,s), 2.02-2.25 (2H, m), 3.16 (2H, s), 4.24 (2H, q, J=7.0 Hz), 7.09 (1H,s), 7.76 (1H, t, J=7.8 Hz), 7.86 (1H, d, J=7.8 Hz), 8.16 (1H, s), 8.26(1H, d, J=7.8 Hz).

Example 483

[3712]3-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-N-methylbenzamide

[3713] 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(0.580 g, 3.03 mmol) was added to a suspension of3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid hydrochloride (1.00 g, 2.33 mmol), 1-hydroxy-1H-benzotriazolemonohydrate (0.392 g, 2.56 mmol) in N,N-dimethylformamide (10 mL) andthe mixture was stirred at room temperature for 30 minutes. To this, 40%methylamine/methanol solution (1.2 mL) was added, and the mixture wasstirred at room temperature further for 2 hours. The reaction solutionwas combined with water, and extracted with ethyl acetate. The extractwas washed with water, and concentrated under reduced pressure. Theresidue was recrystallized from ethyl acetate-hexane to obtain the titlecompound (0.80 g, yield: 84%).

[3714] Melting point: 173-174° C.

[3715]¹H NMR (CDCl₃) δ1.21 (6H, s), 1.28 (6H, s), 1.47 (3H, t, J=7.0Hz), 2.13 (2H, s), 2.61 (2H, s), 2.94 (3H, d, J=5.2 Hz), 4.19 (2H, q,J=7.0 Hz), 6.60 (1H, s), 6.85-6.90 (1H, m), 7.38-7.44 (2H, m), 7.77 (1H,d, J=1.2 Hz), 7.85-7.90 (1m).

Example 484

[3716]N-[2-Amino-2-oxoethyl]-3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide

[3717] Triethylamine (0.810 mL, 5.83 mmol) was added to a suspension of3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid hydrochloride (1.00 g, 2.33 mol) in tetrahydrofuran (10 mL) and themixture was stirred at room temperature for 10 minutes. This was cooledwith ice, treated dropwise with isobutyl chloroformate (0.362 mL, 2.80mmol), and the mixture was stirred with cooling in ice for 45 minutes.

[3718] A solution of glycinamide hydrochloride (0.386 g, 3.50 mmol)dissolved in 2 M aqueous solution of sodium hydroxide (1.75 mL, 3.5mmol) was added to the reaction mixture, and the mixture was stirredwith cooling in ice for 3 hours. The reaction mixture was combined withan aqueous solution of sodium hydrogen carbonate, and extracted withethyl acetate. The extract was washed with water, and concentrated underreduced pressure. The residue was crystallized from ethylacetate-diethyl ether to obtain the title compound (0.82 g, yield: 75%).

[3719] Melting point: 127-128° C.

[3720]¹H NMR (CDCl₃) δ1.22 (6H, s), 1.29 (6H, s), 1.47 (3H, t, J=7.0Hz), 2.14 (2H, s), 2.64 (2H, s), 4.05 (2H, d, J=5.0 Hz), 4.18 (2H, q,J=7.0 Hz), 5.81 (1H, br s), 6.40 (1H, br s), 6.61 (1H, s), 7.41-7.50(2H, m), 7.85-7.99 (3H, m).

Example 485

[3721]N-[3-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoyl]-2-methylalanineethyl ester

[3722] Triethylamine (2.59 mL, 18.6 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.16 g, 6.05 mmol) wereadded to a solution of3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid hydrochloride (2.00 g, 4.65 mmol), 1-hydroxy-1H-benzotriazolemonohydrate (0.784 g, 5.12 mmol) and ethyl 2-aminoisobutyratehydrochloride (1.05 g, 6.05 mmol) in N,N-dimethylformamide (20 mL) andthe mixture was stirred at room temperature for 3 hours. The reactionmixture was combined with water and extracted with ethyl acetate. Theextract was washed with water, and concentrated under reduced pressure.The residue was recrystallized from ethyl acetate-hexane to obtain thetitle compound (1.82 g, yield: 77%).

[3723] Melting point: 155-156° C.

[3724]¹H NMR (CDCl₃) δ1.24-1.30 (15H, m), 1.47 (3H, t, J=7.0 Hz), 1.66(6H, s), 2.16 (2H, s), 2.68 (2H, s), 4.13-4.28 (4H, m), 6.61 (1H, s),6.93 (1H, s), 7.42-7.50 (2H, m), 7.83-7.89 (2H, m).

Example 486

[3725]N-[3-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoyl]-2-methylalaninehydrochloride

[3726] 5 M aqueous solution of sodium hydroxide (3.0 mL) was added to asolution ofN-[3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoyl]-2-methylalanineethyl ester (1.25 g, 2.47 mmol) in ethanol (7 mL) and the mixture wasstirred at room temperature for 3 hours. The reaction solution wascombined with 5 M hydrochloric acid (3.7 mL), and concentrated underreduced pressure. The residue was combined with ethanol and filtered,and the filtrate was concentrated under reduced pressure repetitively 3times. The residue was crystallized from ethyl acetate to obtain thetitle compound (1.28 g, quantitative).

[3727] Melting point: 234-238° C.

[3728]¹H NMR (DMSO-d₆) δ1.22 (12H, s), 1.34 (3H, t, J=6.9 Hz), 45 (6H,s), 2.19 (2H, s), 2.72 (2H, s), 4.12 (2H, q, J=6.9 Hz), 6.85 (1H, s),7.51-7.53 (2H, m), 7.92-7.96 (2H, m), 8.61 (1H, s).

Example 487

[3729] N-(2-Amino-1,1-dimethyl-2-oxoethyl)-3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamides

[3730] A solution ofN-[3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoyl]-2-methylalaninehydrochloride (0.80 g, 1.55 mmol), 1-hydroxy-1H-benzotriazole ammoniumsalt (0.307 g, 2.02mmol) in N,N-dimethylformamide (8 mL) was cooled withice, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.387g, 2.02 mmol) was added thereto, and the mixture was stirred withcooling in ice for 30 minutes. Trlethylamine (0.541 mL, 3.88 mmol) wasadded to the reaction mixture, and the mixture was stirred at roomtemperature for 4 hours. The reaction mixture was combined with a smallamount of water, and concentrated under reduced pressure. The residuewas combined with a saturated aqueous solution of sodium hydrogencarbonate, and extracted with ethyl acetate. The extract was washed withwater, and concentrated under reduced pressure The residue wascrystallized from ethyl acetate-hexane to obtain the title compound(0.50 g, yield: 68%).

[3731] Melting point: 204-206° C.

[3732]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.30 (6H, s), 1.47 (3H, t, J=6.9Hz), 1.69 (6H, s), 2.17 (2H, s), 2.68 (2H, s), 4.18 (2H, q, J=6.9 Hz),5.54 (1H, br s), 6.50 (1H, br s), 6.61 (1H, s), 7.07 (1H, s), 7.42-7.49(2H, m), 7.85-7.89 (2H, m).

Example 488

[3733]3-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine

[3734] A mixture of 1-(7-ethoxy-2,3-dihydro-2,2-dimethyl-5-benzofuranyl)-2-methyl-1-propanol (11.2 g, 42.3 mmol),3-aminobenzonitrile (5.00 g, 42.3 mmol), acetic acid (60 mL) and toluene(75 mL) was cooled with ice, conc. sulfuric acid (6.77 mL, 0.127 mol)was added thereto, and the mixture was stirred at 80° C. for 1 hour. Thereaction solution was allowed to cool to room temperature, combined withwater, and washed with diethyl ether. The aqueous layer was made basicwith conc. aqueous ammonia, and then extracted with ethyl acetate. Theextract was washed with water, and concentrated under reduced pressure.The residue was subjected to a column chromatography on a basic silicagel (hexane/ethyl acetate 2:1) to obtain the title compound (8.17 g,yield: 53%).

[3735] An oil.

[3736]¹H NMR (CDCl₃) δ1.23 (6H, s), 1.32 (6H, s), 1.46 (3H, t, J=7.0Hz), 2.32 (2H, s), 2.65 (2H, s), 3.70 (2H, br s), 4.16 (2H, q, J=7.0Hz), 6.58 (1H, s), 6.70-7.21 (4H, m).

Example 489

[3737]N-[3-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]methanesulfonamide

[3738] A solution of3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine(0.73 g, 2.00 mmol) in pyridine (5 mL) was cooled with ice, treateddropwise with methanesulfonyl chloride (0.186 mL, 2.40 mmol), and themixture was stirred with cooling in ice for 1 hour. The reactionsolution was combined with a saturated aqueous solution of sodiumhydrogen carbonate and extracted with ethyl acetate. The extract waswashed with water and concentrated under reduced pressure. The residuewas subjected to a column chromatography on a basic silica gel (ethylacetate/methanol 97:3), crystallized from ethyl acetate-hexane to obtainthe title compound (0.52 g, yield: 59%).

[3739] Melting point: 181-182° C.

[3740]¹H NMR (CDCl₃) δ1.27 (6H br s), 1.32 (6H, s), 1.46 (3H, t, J=7.2Hz), 2.23 (2H, s), 2.71 (2H, s), 2.77 (3H, s), 4.18 (2H, q, J=7.2 Hz),6.60 (1H, s), 7.08-7.14 (1H, m), 7.22-7.35 (4H, m).

Example 490

[3741]N-[3-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-N-(methylsulfonyl)methanesulfonamide

[3742] The title compound was obtained from3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamineand methanesulfonyl chloride by the method similar to that in EXAMPLE30. Yield: 53%.

[3743] Melting point: 183-184° C. (ethyl acetate-hexane).

[3744]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.31 (6H, s), 1.46 (3H, t, J=10 6.9Hz), 2.23 (2H, br s), 2.68 (2H, s), 3.40 (6H, s), 4.18 (2H, q, J=6.9Hz), 6.61 (1H, s), 7.29 (1H, t, J=1.5 Hz), 7.35-7.40 (1H, m), 7.52 (1H,t, J=7.8 Hz), 7.61 (1H, dt, J=7.8 Hz, 1.5 Hz).

Example 491

[3745]N-[3-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2-(methylthio)acetamide

[3746] By the method similar to that in EXAMPLE 30,3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamineand chloroacetyl chloride were employed to obtain2-chloro-N-[3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]acetamide.This was converted to the title compound by the method similar to thatin EXAMPLE 38.

[3747] yield: 50%.

[3748] Melting point: 162-163° C. (ethyl acetate-hexane).

[3749]¹H NMR (CDCl₃) δ1.24 (6H, s), 1.32 (6H, s), 1.46 (3H, t, J=6.9Hz), 2.19 (3H, s), 2.28 (2H, s), 2.67 (2H, s), 3.34 (2H, s), 4.18 (2H,q, J=6.9 Hz), 6.60 (1H, s), 7.12 (1H, d, J=7.2 Hz), 7.36 (1H, t, J=7.2Hz), 7.43 (1H, s), 7.84 (1H, d, J=7.2 Hz), 8.82 (1H, s).

Example 492

[3750]N-[3-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2-(methylsulflnyl)acetamide

[3751] The title compound was obtained fromN-[3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2-(methylthio)acetamideby the method similar to that in EXAMPLE 39. Yield: 67%.

[3752] Melting point: 114-118° C. (ethyl acetate-hexane).

[3753]¹H NMR (CDCl₃) δ1.13 (6H, s), 1.22 (6H, s), 1.33 (3H, t, J=7.0Hz), 2.28 (2H, s), 2.62 (2H, s), 2.69 (3H, s), 3.73 (1H, d, J=12.8 Hz),3.93 (1H, d, J=12.8 Hz), 4.09 (2H, q, J=7.0 Hz), 6.78 (1H, s), 7.06 (1H,d, J=7.6 Hz), 7.32-7.39 (1H, m), 7.61-7.65 (2H, m), 10.40 (1H, s).

Example 493

[3754]N-(Hydroxymethyl)-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamlde

[3755] A suspension of3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide(0.50 g, 1.32 mmol), 37% formalin (1.07 g, 13.2 mmol) and potassiumcarbonate (0.365 g, 2.64 mmol) in acetonitrile (5 mL) was stirred at 60°C. for 3 hours, and then allowed to stand for 1 month. The reactionmixture was combined with a saturated aqueous solution of sodiumhydrogen carbonate, and extracted with ethyl acetate. The extract waswashed with water, and concentrated under reduced pressure. The residuewas subjected to a column chromatography on a silica gel (ethylacetate/methanol 19:1) to obtain the title compound (0.40 g, yield:74%).

[3756] Amorphous.

[3757]¹H NMR (CDCl₃) δ1.23 (6H, s), 1.29 (6H, s), 2.14 (2H, s), 2.65(2H, s), 3.93 (3H, s), 4.87 (2H, d, J=6.2 Hz), 6.62 (1H, s), 7.39-7.48(2H, m), 7.83-7.89 (2H, m), 8.05-8.11 (1H, m).

Example 494

[3758]N-Methyl-3-(3,4,8,9-tetrahydro-4-hydroxy-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide

[3759] The title compound was obtained fromN-methyl-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamideby the method similar to that in EXAMPLE 291. yield: 351.

[3760] Melting point: 215-216° C. (ethyl acetate).

[3761]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.29 (6H, s), 2.16 (2H, s), 2.95(3H, d, J=4.4 Hz), 3.95 (3H, s), 4.44 (1H, s), 6.98 (1H, s), 7.18 (1H,br s), 7.42-7.50 (2H, m), 7.81 (1H, s), 7.87-7.91 (1H, m).

Example 495

[3762]N-Methyl-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-4-oxofuro[2,3-h]isoquinolin-1-yl)benzamide

[3763] The title compound was obtained fromN-methyl-3-(3,4,8,9-tetrahydro-4-hydroxy-6-methoxy-3,3,8,8-tetramethylfuro[2.3-h]isoquinolin-1-yl)benzamideby the method similar to that in EXAMPLE 294. Yield: 45%.

[3764] Melting point: 229-231° C. (ethyl acetate-diisopropyl ether).

[3765]¹H NMR (CDCl₃) δ1.34 (6H, s), 1.52 (6H, s), 2.17 (2H, s), 3.00(3H, d, J=4.8 Hz), 4.00 (3H, s), 6.36-6.48 (1H, m), 7.44-7.59 (3H, m),7.78 (1H, s), 7.85-7.91 (1H, m).

Example 496

[3766]N-(2-Amino-1,1-dimethyl-2-oxoethyl)-3-(3,4,8,9-tetrahydro-4-hydroxy-6-methoxy-3,3,8,8-tetramethylfurot[2,3-h]isoqulnolin-1-yl)benzamide

[3767] The title compound was obtained fromN-(2-amino-1,1-dimethyl-2-oxoethyl)-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamideby the method similar to that in EXAMPLE 291. Yield: 64%.

[3768] Melting point: 155-158° C. (ethyl acetate).

[3769]¹H NMR (CDCl₃) δ1.25-1.31 (12H, m), 1.69 (6H, s), 2.20 (2H, s),3.96 (3H, s), 4.48 (1H, s), 5.82 (1H, br s), 6.77 (1H, br s), 7.03 (1H,s), 7.43-7.52 (3H, m), 7.91 (2H, s).

Example 497

[3770]N-(2-Amino-1,1-dimethyl-2-oxoethyl)-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-4-oxofuro[2,3-h]isoquinolin-1-yl)benzamide

[3771] The title compound was obtained fromN-(2-amino-1,1-dimethyl-2-oxoethyl)-3-(3,4,8,9-tetrahydro-4-hydroxy-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamideby the method similar to that in EXAMPLE 294. yield: 52%.

[3772] Melting point: 180-181° C. (ethyl acetate).

[3773]¹H NMR (DMSO-d₆) 1.26 (6H, s), 1.41 (6H, s), 1.45 (6H, s), 2.24(2H, s), 3.91 (3H, s), 6.85 (1H, br s), 7.19 (1H, br s), 7.47-7.55 (3H,m), 7.90-7.98 (2H, m), 8.29 (1H, br s).

Example 498

[3774]3-(Bromomethyl)-6-ethoxy-3,4,8,9-tetrahydro-3,8,8-trimethylfuro[2,3-h]isoquinolinehydrochloride

[3775] Benzonitrile (20mL) was cooled to −5° C., aluminum chloride (2.38g, 17.9 mmol) was added thereto and the mixture was stirred.

[3776] Immediately after adding7-ethoxy-2,3-dihyro-2,2-dimethyl-5-(2-methyl-2-propenyl)benzofuran (2.20g, 8.93 mmol), bromine (0.46 mL, 8.93 mmol) was added dropwise to themixture, and the mixture was stirred at −5° C. for 1 hour and then atroom temperature further for 3 hours. The reaction mixture was pouredinto 1 M hydrochloric acid, and washed with diisopropyl ether. Theaqueous layer was made basic with conc. aqueous ammonia, and extractedwith ethyl acetate. The extract was washed with water, and concentratedunder reduced pressure. The residue was subjected to a columnchromatography on a silica gel (hexane/ethyl acetate 17:3 followed by7:3) to obtain3-(bromomethyl)-6-ethoxy-3,4,8,9-tetrahydro-3,8,8-trimethylfuro[2,3-h]isoquinoline(1.41 g, yield: 37%).

[3777] An oil.

[3778]¹H NMR (CDCl₃) δ1.31 (6H, s), 1.34 (3H, s), 1.47 (3H, t, J=7.2Hz), 2.18 (2H, s), 2.78 (1H, d, J=15.9 Hz), 2.93 (1H, d, J=15.9 Hz),3.40 (1H, d, J=9.9 Hz), 3.55 (1H, d, J=9.9 Hz), 4.19 (2H, q, J=7.2 Hz),6.65 (1H, s), 7.39 (5H, s).

[3779] This was converted into a hydrochloride salt which was trituratedfrom diethyl ether to obtain the title compound (1.40 g, yield from7-ethoxy-2.3-dihydro-2,2-dimethyl-5-(2-methyl-2-propenyl)benzofuran:34%). An aliquot was crystallized from ethyl acetate.

[3780] Melting point: 156-159° C.

[3781]¹H NMR-(DMSO-d₆) δ1.22 (3H, s), 1.24 (3H, s), 1.37 (3H, t, J=6.9Hz), 1.59 (3H, s), 2.17 (2H, s), 3.35 (2H, s), 3.83 (1H, d, J=10.8 Hz),3.92 (1H, d, J=10.8 Hz), 4.24 (2H, q, J=6.9 Hz), 7.11 (1H, s), 7.59-7.78(5H, m).

Example 499

[3782]6-Ethoxy-3,4,8,9-tetrahydro-N,N,3,8,8-pentamethyl-3-furo[2,3-h]isoquinolinemethanaminedihydrochloride

[3783] A mixture of3-(bromomethyl)-6-ethoxy-3,4,8,9-tetrahydro-3,8,8-trimethylfuro[2,3-h]isoquinolinehydrochloride (0.50 g, 1.08 mmol), 40% aqueous solution of methylamine(2 mL) and N,N-dimethylacetamide (3 mL) was stirred at 180° C. for 14hours in a sealed tube. The reaction solution was combined with asaturated aqueous solution of sodium hydrogen carbonate, and extractedwith ethyl acetate. The extract was washed with water, and concentratedunder reduced pressure. The residue was subjected to a columnchromatography on a silica gel (hexane/ethyl acetate 1:1 followed byhexane/ethyl acetate/triethylamine 92:5:3), and then to a columnchromatography on a basic silica gel (hexane/ethyl acetate 4:1) toobtain6-ethoxy-3,4,8,9-tetrahydro-N,N,3,8,8-pentamethyl-3-furo[2,3-h]isoquinolinemethanamine(0.22 g, yield: 52%).

[3784] An oil.

[3785]¹H NMR (CDCl₃) δ1.22-1.32 (9H, m), 1.45 (3H, t, J=7.0 Hz), 2.18(2H, s), 2.31 (6H, s), 2.35-2.51 (2H, m), 2.64 (1H, d, J=15.6 Hz), 2.97(1H, d, J=15.6 Hz), 4.17 (2H, q, J=7.0 Hz), 6.62 (1H, s), 7.38 (5H, s).

[3786] This was converted into a hydrochloride salt, crystallized fromethyl acetate to obtain the title compound (0.20 g, yield from3-(bromomethyl)-6-ethoxy-3,4,8,9-tetrahydro-3,8,8-trimethylfuro[2,3-h]isoquinolinehydrochloride: 40%).

[3787] Melting point: 145-147° C.

[3788]¹H NMR (DMSO-d₆) δ1.23 (3H, s), 1.25 (3H, s), 1.38 (3H, t, J=6.9Hz), 1.54-1.62 (3H, m), 2.11 (1H, d, J=16.2 Hz), 2.28 (1H, d, J=16.2Hz), 2.91 (6H, s), 3.20 (2H, s), 3.60 (2H, s), 4.23 (2H, q, J=6.9 Hz),7.03 (1H, s), 7.59-7.69 (5H, m).

Example 500

[3789]6-Ethoxy-N-ethyl-3,4,8,9-tetrahydro-N,3,8,8-tetramethyl-3-furo[2,3-h]isoquinolinemethanaminedihydrochloride

[3790] The title compound was obtained from3-(bromomethyl)-6-ethoxy-3,4,8,9-tetrahydro-3,8,8-trimethylfuro[2,3-h]isoquinolinehydrochloride and N-ethylmethylamine by the method similar to that inEXAMPLE 499. Yield: 33%.

[3791] Melting point: 146-149° C. (ethyl acetate).

[3792]¹H NMR (DMSO-d₆) δ1.23 (6H, s), 1.27 (3H, t, J=7.4 Hz), 1.38 (3H,t, J=6.8 Hz), 1.58 (3H, s), 2.13 (1H, d, J=16.4 Hz), 2.26 (1H, d, J=16.4Hz), 2.89 (3H, s), 3.20-3.61 (6H, m), 4.23 (2H, q, J=6.8 Hz), 7.03 (1H,s), 7.60-7.65 (5H, m).

Example 501

[3793]O-[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]dimethylcarbamothioate hydrochloride

[3794]3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenol(3.50 g, 9.96 mmol) was added to a solution of potassium hydroxide (587mg, 10.5 mmol) in water (30 mL)-acetone (30 mL), and the mixture wasstirred at room temperature for 20 minutes. With cooling in ice,N,N-dimethythiocarbamoyl chloride (1.42 g, 11.5 mmol) was added to themixture, and the mixture was stirred at room temperature for 3 hours.Acetone was distilled off under reduced pressure, the mixture was madebasic by adding 1 M aqueous solution of sodium hydroxide, and extractedtwice with ethyl acetate. The combined organic layer was washed with 1 Maqueous solution of sodium hydroxide and brine, dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas subjected to a column chromatography on a basic silica gel(hexane/ethyl acetate 5:1 followed by 3:1) to obtain 3.40 g of a freebase of the title compound. 753 mg of them was dissolved in ethylacetate, combined with 4 M hydrogen chloride/ethyl acetate solution,concentrated under reduced pressure, triturated from diethyl ether toobtain the title compound (745 mg, yield: 57%).

[3795] Amorphous.

[3796]¹H NMR (DMSO-d₆) δ1.23 (6H, s), 1.41 (3H, s), 1.47 (3H, s),2.05-2.75 (2H, m), 3.17 (2H, s), 3.20-3.50 (6H, m), 3.94 (3H, s), 7.09(1H, s), 7.37-7.54 (3H, m), 7.67-7.74 (1H, m), 12.70 (1H, br s).

Example 502

[3797]2-[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenoxy]acetamide

[3798] Potassium tert-butoxide (380 mg, 3.37 mmol) was added to asolution of3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenol(215 mg, 0.612 mmol) in N,N-dimethylformamide (2 mL) with cooling inice, and the mixture was stirred at room temperature for 1 hour.2-Bromoacetamide (279 mg, 2.02 mmol) was added and the mixture wasstirred at room temperature for 2 hours, and then stirred at 90° C. for24 hours. Water was poured into the reaction mixture, which was thenextracted twice with ethyl acetate. The combined organic layer waswashed with 1 M aqueous solution of sodium hydroxide and brine, driedover sodium sulfate, filtered, and concentrated under reduced pressure.The residue was subjected to a column chromatography on a basic silicagel (hexane/ethyl acetate 1:2 followed by hexane/ethylacetate/triethylamine 15:30:1:), crystallized from diethyl ether-hexaneto obtain the title compound (130 mg, yield: 52%).

[3799] Melting point: 172-174° C.

[3800]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.32 (6H, s), 2.24 (2H, br s), 2.69(2H, s), 3.93 (3H, s), 4.53 (2H, s), 5.63 (1H, br s), 6.60 (1H, br s),6.62 (1H s), 6.93-7.05 (3H, m), 7.29-7.37 (1H, m).

Example 503

[3801]N-Methyl-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenesulfonamidehydrochloride

[3802] A suspension of 3-cyano-N-methylbenzenesulfonamide (2.10 g, 10.7mmol) in acetic acid (10 mL)-toluene (17 mL) was treated with conc.sulfuric acid (1.2 mL, 22.5 mmol) with cooling in ice,1-(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-2-methyl-1-propanol(3.20 g, 12.8 mmol) was added thereto at room temperature, and themixture was stirred at 80° C. for 1 hour. Ice water was poured into thereaction mixture, which was then washed with diethyl ether. The aqueouslayer was neutralized with conc. aqueous ammonia, and extracted twicewith ethyl acetate. The combined organic layer was washed with brine,dried over sodium sulfate, filtered, and concentrated under reducedpressure. The residue was subjected to a column chromatography on asilica gel (hexane/ethyl acetate 1:1 followed by hexane/ethylacetate/triethylamine 25:25:1) to obtain a free base of the titlecompound. This was dissolved in ethyl acetate, combined with 4 Mhydrogen chlorlde/ethyl acetate solution, concentrated under reducedpressure, and crystallized from ethanol-ethyl acetate to obtain thetitle compound (3.19 g, yield: 64%).

[3803] Melting point: 164-167° C.

[3804]¹H NMR (DMSO-d₆) δ1.22 (6H, s), 1.46 (6H, br s), 2.13 (2H, s),2.45 (3H, d, J=4.8 Hz), 3.04-3.30 (3H, m), 3.95 (3H, s), 7.11 (1H, s),7.76-8.26 (4H, m).

Example 504

[3805]2-[(Methyl)[[(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]sulfonyl]amino]aceticacid ethyl ester hydrochloride

[3806] Sodium hydride (66% dispersion in oil) (148 mg, 4.07 mmol) wasadded to a solution ofN-methyl-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenesulfonamidehydrochloride (900 mg, 1.94 mmol) in N,N-dimethylformamide (9 mL) withcooling in ice, and the mixture was stirred-at room temperature for 30minutes. With cooling in ice, ethyl bromoacetate (0.23 mL, 2.03 mmol)was added to the mixture and the mixture was stirred at room temperaturefor 5 hours. Water was poured into the reaction mixture, which wasextracted twice with ethyl acetate. The combined organic layer waswashed with water and brine, dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was subjected to acolumn chromatography on a basic silica gel (hexane/ethyl acetate 3:1)to obtain a free base of the title compound. This was dissolved in ethylacetate, combined with 4 M hydrogen chloride/ethyl acetate solution,concentrated under reduced pressure, crystallized from ethyl acetate toobtain the title compound (680 mg, yield: 64%).

[3807] Melting point: 122-125° C.

[3808]¹H NMR (DMSO-d₆) δ1.17 (3H, t, J=7.0 Hz), 1.22 (6H, s), 1.46 (6H,br s), 2.17 (2H, s), 2.87 (3H, s), 3.17 (2H, s), 3.94 (3H, s), 4.06 (2H,q, J=7.0 Hz), 4.12 (2H, s), 7.11 (1H, s), 7.81-7.92 (2H, m), 8.09-8.13(2H, m).

Example 505

[3809]2-[(Methyl)[[3-(3,4,8,9,-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]disoquinolin-1-yl)phenyl]sulfonyl]amino]acetamide

[3810] 5 M aqueous solution of sodium hydroxide (1.5 mL) was added to asolutiro of2[-(methyl)-[[(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]sulfonyl]amino]aceticacid ethyl ester hydrochloride (464 mg, 0.842 mmol) in ethanol (1.5 mL)and the mixture was stirred at room temperature for 1 hour. Afterdistilling ethanol off under reduced pressure, water was added and themixture was adjusted at pH 6 with 5 M hydrochloric acid, and extractedtwice with ethyl acetate-tetrahydrofuran. The combined organic layer wasdried over sodium sulfate, filtered, concentrated under reduced pressureto obtain2-[(methyl)[[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]sulfonyl]amino]acetic acid (394 mg). 1-Ethyl-3-(3-dimethylaminopropyl)carbodumidehydrochloride (199 mg, 1.04 mmol) and 1-hydroxy-1H-benzotriazolemonohydrate (123 mg, 0.802 mmol) were added to a solution of theresultant acetic acid derivative (390 mg) in N,N-dimethylformamide (2mL) and the mixture was stirred at room temperature for 30 minutes.After cooling with ice, conc. aqueous ammonia (0.5 mL) was added to themixture, and the mixture was stirred at room temperature for 1 hour.Water was poured into the reaction mixture, which was then extractedtwice with ethyl acetate-tetrahydrofuran. The combined organic layer waswashed with a brine, dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was subjected to acolumn chromatography on a basic silica gel (hexane/ethyl acetate 3:1),crystallized from ethyl acetate-hexane to obtain the title compound (55mg, yield: 14%).

[3811] Melting point: 105-107° C.

[3812]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.33 (6H, s), 2.16 (2H, s), 2.72(2H, s), 2.86 (3H, s), 3.66 (2H, s), 3.93 (3H, s), 5.58 (1H, br s), 6.58(1H, br s), 6.64 (1H, s), 7.59-7.86 (4H, m).

Example 506

[3813]N-[3-[[[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolinyl)phenyl]sulfonyl]amino]phenyl]acetamide hydrochloride

[3814] A solution ofN-[3-[(3-cyanobenzenesulfonyl)amino]phenyl]acetamide (1.39 g, 4.41 mmol)in acetic acid (5 mL)-toluene (8 mL) was treated dropwise with conc.sulfuric acid (0.52 mL, 9.70 mmol) with cooling in ice, and1-(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-2-methyl-1-propanol(1.32 g, 5.29 mmol) was added thereto at room temperature, and themixture was stirred at 60° C. for 3 hours. Ice water was poured into thereaction mixture, which was washed with diethyl ether. The aqueous layerwas neutralized with conc. aqueous ammonia, and extracted twice withethyl acetate. The combined organic layer was washed with brine, driedover sodium sulfate, filtered and concentrated under reduced pressure.The residue was subjected to a column chromatography on a silica gel(hexane/ethyl acetate 1:2 followed by 1:3) to obtain a free base of thetitle compound. This was dissolved in ethyl acetate, combined with 4 Mhydrogen chloride/ethyl acetate solution, concentrated under reducedpressure, triturated from diethyl ether to obtain the title compound(815 mg, yield: 48%).

[3815] Amorphous.

[3816]¹H NMR (DMSO-d₆) δ1.09 (6H, s), 1.45 (6H, s), 1.73-2.00 (2H, m),1.94 (3H, s), 3.17 (2H, s), 3.93 (3H, s), 6.65-6.78 (1H, m), 7.10-7.13(3H, m), 7.66 (1H, s), 7.80-7.90 (2H, m), 8.05-8.20 (2H, m), 10.05 (1H,s), 10.58 (1H, s).

Example 507

[3817]2-[[[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]sulfonyl]amino]acetamidehydrochloride

[3818] A suspension of 2-[[(3-cyanobenzene)sulfonyl]amino]acetamide (180mg, 0.752 mmol) in acetic acid (1 ml)-toluene (1.6 mL) was treateddropwise with conc. sulfuric acid (0.088 mL, 1.65 mmol) with cooling inice,1-(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-2-methyl-1-propanol(226 mg, 0.903 mmol) was added thereto at room temperature, and themixture was stirred at 60° C. for 2 hours. Water was poured into thereaction mixture, which was washed twice with diethyl ether. The aqueouslayer was neutralized with conc. aqueous ammonia, and extracted twicewith ethyl acetate. The combined organic layer was washed with brine,dried over sodium sulfate, filtered and concentrated under reducedpressure. The residue was subjected to a column chromatography on asilica gel (ethyl acetate followed by ethyl acetate/methanol 10:1) toobtain a free base of the title compound. This was dissolved in ethylacetate, combined with 4 M hydrogen chloride/ethyl, acetate solution,concentrated under reduced pressure, triturated from diethyl ether toobtain the title compound (189 mg, yield: 50%).

[3819] Amorphous.

[3820]¹H NMR (DMSO-d₆) δ1.22 (6H, s), 1.46 (6H, br s), 2.00-2.30(2H, m),3.17 (2H, s), 3.30-3.60 (2H, m), 3.94 (3H, s), 7.10 (2H, s), 7.42 (1H,s), 7.80-7.87 (2H, m), 8.04 (1H, s), 8.11-8.25 (2H, m).

Example 508

[3821]N-(Hexahydro-2-oxo-1H-azepin-3-yl)-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenesulfonamidehydrochloride

[3822] A suspension of3-cyano-N-(hexahydro-2-oxo-1H-azepin-3-yl)benzenesulfonamide (360 mg,1.23 mmol) in acetic acid (2 mL)-toluene (3.2 mL) was treated dropwisewith conc. sulfuric acid (0.14 mL, 2.71 mmol) with cooling in ice, andstirred at room temperature for 5 minutes.1-(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-2-methyl-1-propanol(369 mg, 1.47 mmol) was added to the mixture, and the mixture wasstirred at 65° C. for 3 hours. Water was poured into the reactionmixture, which was washed twice with diethyl ether. The aqueous layerwas neutralized with conc. aqueous ammonia, and extracted twice withethyl acetate. The combined organic layer was washed with brine, driedover sodium sulfate, filtered and concentrated under reduced pressure.The residue was subjected to a column chromatography on a basic silicagel (hexane/ethyl acetate 1:2) to obtain a free base of the titlecompound. This was dissolved in ethyl acetate, combined with 4 Mhydrogen chloride/ethyl acetate solution, concentrated under reducedpressure, triturated with diethyl ether to obtain the title compound(270 mg, yield: 39%).

[3823] Amorphous.

[3824]¹H NMR (DMSO-d₆) δ1.22 (6H, s), 1.44 (3H, s), 1.45-1.85 (4H, m),1.47 (3H, s), 2.00-2.35 (2H, m), 2.90-3.15 (2H, m), 3.16 (2H, s),3.39-3.45 (2H, m), 3.94 (3H, s), 4.00-4.15 (1H, m), 7.10 (1H, s),7.65-7.90 (2H, m), 7.82 (2H, br s), 8.03-8.20 (2H, m).

Example 509

[3825]S-[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]dimethylcarbamothioate hydrochloride

[3826] A suspension of S-(3-cyanophenyl) dimethylcarbamothioate (637 mg,3.09 mmol) in acetic acid (4 mL)-toluene (6.5 mL) was treated dropwisewith conc. sulfuric acid (0.36 mL 6.80 mmol) with cooling in ice,1-(2,3-dihydro-7-methoxy-2,2-dimethyi-5-benzofuranyl)-2-methyl-1-propanol(928 mg, 3.71 mmol) was added thereto at room temperature, and themixture was stirred at 80° C. for 1 hour. Ice water was poured into thereaction mixture, which was then washed with diethyl ether. The aqueouslayer was neutralized with conc. aqueous ammonia, and extracted twicewith ethyl acetate. The combined organic layer was washed with brine,dried over sodium sulfate, filtered and concentrated under reducedpressure. The residue was subjected to a column chromatography on abasic silica gel (hexane/ethyl acetate 5:1 followed by 3:1) to obtain afree base of the title compound as an amorphous material.

[3827]¹H NMR (CDCl₃) δ1.24 (6H, s), 1.33 (6H, s), 2.39 (2H, br s), 2.67(2H, s), 3.03 (6H, br s), 3.91 (3H, s), 6.59 (1H, s), 7.38-7.58 (4H, m).

[3828] This was dissolved in ethyl acetate, combined with 4 M hydrogenchloride/ethyl acetate solution, concentrated under reduced pressure,triturated with diethyl ether to obtain the title compound (618 mg,yield: 42%).

[3829] Amorphous.

[3830]¹H NMR (DMSO-d₆) δ1.23 (6H, s), 1.42 (3H, s), 1.45 (3H, s), 2.13(1H, br d, J=15.8 Hz), 2.40-2.60 (1H, m), 2.94 (3H, s), 3.00-3.50 (2H,m), 3.05 (3H, s), 3.94 (3H, s), 7.09 (1H, s), 7.68-7.80 (4H, m).

Example 510

[3831]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-[3-(methylthio)phenyl]furo[2,3-h]isoquinolinehydrochloride

[3832] 28% sodium methoxide/methanol solution (2 mL) was added to asolution ofS-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]dimethylcarbamothioate(1.12 g, 2.55 mmol) in N,N-dimethylformamide (10mL) with cooling in ice, and the mixture was stirred at room temperaturefor 1 hour. Ice water was poured into the reaction mixture, which wasneutralized with 5 M hydrochloric acid, and extracted three times withethyl acetate. The combined organic layer was washed with brine, driedover sodium sulfate, filtered and concentrated under reduced pressure.The residue was dissolved in N,N-dimethylformamide (10 mL), sodiumhydride (66% dispersion in oil) (93 mg, 2.55 mmol) was added thereto andthe mixture was stirred at room temperature for 20 minutes. With coolingin ice, iodomethane (0.16 mL, 2.55 mmol) was added to the mixture andthe mixture was stirred at room temperature for 2 hours.

[3833] Water was poured into the reaction mixture which was extractedtwice with ethyl acetate. The combined organic layer was washed withbrine, dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was subjected to a column chromatographyon a basic silica gel (hexane/ethyi acetate 10:1) to obtain a free baseof the title compound as an amorphous material.

[3834]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.33 (6H, s), 2.24 (2H, s), 2.49(3H, s), 2.69 (2H, s), 3.93 (3H, s), 6.61 (1H, s), 7.13-7.31 (4H, m).

[3835] This was dissolved in ethyl acetate, combined with 4 M hydrogenchloride/ethyl acetate solution, concentrated under reduced pressure,crystallized from ethyl acetate to obtain the title compound (247 mg,yield: 23%).

[3836] Melting point: 130-140° C.

[3837]¹H NMR (DMSO-d₆) δ1.24 (6H, s), 1.44 (6H, s), 2.25 (2H, s), 2.55(3H, s), 3.14 (2H, s), 3.94 (3H, s), 7.09 (1H, s), 7.31-7.35 (1H, m),7.51-7.63 (3H, m).

Example 511

[3838]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-[3-(methylsulfinyl)phenyl]furo[2,3-h]isoquinolinehydrochloride

[3839] A solution of sodium metaperiodate (404 mg, 1.89 mmol) in water(2.5 mL) was added to a solution of3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-[3-(methylthio)phenyl]furo[2,3-h]isoquinoline(288 mg, 0.755 mmol) in methanol (3.5 mL) and the mixture was stirred atroom temperature for 1 hour. Water was poured into the reaction mixture,which was combined with sodium hydrogen carbonate, and extracted twicewith ethyl acetate. The combined organic layer was washed with water andbrine, dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was subjected to a column chromatographyon a basic silica gel (hexane/ethyl acetate 2:1 followed by 1:1) toobtain a free base of the title compound. This was dissolved in ethylacetate, combined with 4 M hydrogen chloride/ethyl acetate solution,concentrated under reduced pressure, triturated with diethyl ether toobtain the title compound (257 mg, yield: 78%).

[3840] Amorphous.

[3841]¹H NMR (DMSO-d₆) δ1.22 (6H, s), 1.47 (6H, s), 2.15 (2H, s), 2.85(3H, s), 3.17 (2H, s), 3.94 (3H, s), 7.11 (1H, s), 7.76-8.05 (4H, m).

Example 512

[3842]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-[3-(methylsulfonyl)phenyl]furo[2,3-h]isoquinolinehydrochloride

[3843] A solution of sodium metaperiodate (517 mg, 2.42 mmol) in water(2 mL) was added to a solution of3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-[3-(methylthio)phenyl]furo[2,3-h]isoquinolinehydrochloride (202 mg, 0.483 molo) in methanol (3 mL) and the mixturewas stirred at 60° C. for 4 hours. Water was poured into the reactionmixture, which was combined with sodium hydrogen carbonate and extractedtwice with ethyl acetate. The combined organic layer was washed withwater and brine, dried over sodium sulfate, filtered and concentratedunder reduced pressure. The residue was subjected to a columnchromatography on a basic silica gel (hexane/ethyl acetate 3:1) toobtain a free base of the title compound. This was dissolved in ethylacetate, combined with 4 M hydrogen chloride/ethyl acetate solution,concentrated under reduced pressure, crystallized from ethanol-ethylacetate-diisopropyl ether to obtain the title compound (171 mg, yield:79%).

[3844] Melting point: 141-145° C.

[3845]¹H NMR (DMSO-d₆) δ1.22 (6H, s), 1.47 (6H, s), 2.14 (2H, s), 3.16(2H, s), 3.34 (3H, s), 3.94 (3H, s), 7.11 (1H, s), 7.86-8.00 (2H, m),8.23-8.27 (2H, m).

Example 513

[3846]2-[[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]thio]acetamide

[3847]S-[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]dimethylcarbamothioate (1.62 g, 3.69 mmol) was added to a solution of28% sodium methoxide/methanol solution (1.43 g, 7.39 mmol) inN,N-dimethylformamide (8 mL) with cooling in ice, and the mixture wasstirred at room temperature for 30 minutes. Water was poured into thereaction mixture, which was extracted twice with ethylacetate-tetrahydrofuran. The combined organic layer was washed withbrine, dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was subjected to a column chromatographyon a basic silica gel (hexane/ethyl acetate 1:2) to obtain an amorphousmaterial (1.25 g). An Aliquot (369 mg) was crystallized from ethylacetate-hexane to obtain the title compound (298 mg, yield: 64%).

[3848] Melting point: 118-120° C.

[3849]¹H NMR (CDCl₃) δ1.27 (6H, s), 1.33 (6H, s), 2.20 (2H, s), 2.71(2H, s), 3.66 (2H, s), 3.93 (3H, s), 5.44 (1H, br s), 6.62 (1H, s), 6.81(1H, br s), 7.21-7.43 (4H, m).

Example 514

[3850]2-[[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]sulfinyl]acetamidehydrochloride

[3851]

[3852] A solution of sodium metaperiodate (655 mg, 3.06 mmol) in water(2.5 mL) was added to a solution of2-[[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]thio]acetamide(401 mg, 0.945 mmol) in methanol (4 mL) and the mixture was stirred atroom temperature for 3 hours. Water was poured into the reactionmixture, which was neutralized with sodium hydrogen carbonate, andextracted three times with ethyl acetate. The combined organic layer waswashed with water and brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure The residue was subjected to acolumn chromatography on a basic silica gel (hexane/ethyl acetate 1:3followed by ethyl acetate) to obtain a free base of the title compound.This was dissolved in ethyl acetate, combined with 4 M hydrogenchloride/ethyl acetate solution, concentrated under reduced pressure,triturated with diethyl ether to obtain the title compound (357 mg,yield: 794).

[3853] Amorphous.

[3854]¹H NMR (DMSO-d₆) δ1.23 (6H, s), 1.47 (6H, s), 2.17 (2H, s), 3.17(2H, s), 3.80 (1H, br d, J=13.4 Hz), 3.94 (3H, s), 4.04 (1H, d, J=13.4Hz), 7.10 (1H, s), 7.36 (1H, s), 7.75-8.03 (5H, m).

Example 515

[3855]2-[[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]sulfonyl]acetamidehydrochloride

[3856] A solution of sodium metaperiodate (1.22 g, 5.72 mmol) in water(4 mL) was added to a solution of2-[[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]thio]acetamide(486 mg, 1.14 mmol) in methanol (6 mL) and the mixture was stirred at70° C. for 6 hours. Water was poured into the reaction mixture, whichwas combined with sodium hydrogen carbonate, and extracted twice withethyl acetate. The combined organic layer was washed with water andbrine, dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was subjected to a column chromatographyon a basic silica gel (hexane/ethyl acetate 1:3) to obtain a free baseof the title compound. This was dissolved in ethyl acetate, combinedwith 4 M hydrogen chloride/ethyl acetate solution, concentrated underreduced pressure, triturated with diethyl ether to obtain the titlecompound (370 mg, yield: 66%).

[3857] Amorphous.

[3858]¹H NMR (DMSO-d₆) δ1.21 (6H, s), 1.47 (6H, s), 200-2.40 (2H, m),3.17 (2H, s), 3.94 (3H, s), 4.30-4.60 (2H, m), 7.10 (1H, s), 7.35 (1H,s), 7.80 (1H, s), 7.84-7.98 (2H, m), 8.15-8.19 (2H, m).

Example 516

[3859]3-Chloro-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-1-propanesulfonamide

[3860] A solution of3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine(729 mg, 2.08 mmol) and triethylamine (0.32 mL, 2.29 mmol) intetrahydrofuran (7 mL) was treated dropwise with 3-chloropropanesulfonylchloride (0.25 mL, 2.08 mmol) with cooling in ice, and stirred at roomtemperature for 3 hours. Ice water was poured into the reaction mixture,which was extracted twice with ethyl acetate. The combined organic layerwas washed with brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was subjected to acolumn chromatography on a silica gel (hexane/ethyl acetate 2:1 followedby hexane/ethyl acetate/triethylamine 25:25:1) to obtain an oil (820mg). An aliquot (520 mg) was crystallized from ethyl acetate-hexane toobtain the title compound (453 mg, yield: 70%).

[3861] Melting point: 163-165° C.

[3862]¹H NMR (CDCl₃) δ1.27 (6H, s), 1.33 (6H, s), 2.17-2.31 (2H, m),2.24 (2H, s), 2.72 (2H, s), 3.12 (2H, t, J=6.5 Hz), 3.64 (2H, t, J=6.2Hz), 3.93 (3H, s), 6.61 (1H, s), 7.12-7.39 (4H, m).

Example 517

[3863]2-[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]isothiazolidine1,1-dioxide

[3864] 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.11 mL, 0.753 mmol) wasadded to a solution of3-chloro-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-1-propanesulfonamide(352 mg, 0.717 mmol) in toluene (3 mL) and the-mixture was stirred at110° C. for 1 hour. Water was poured into the reaction mixture. Themixture was neutralized with 1 M hydrochloric acid, and extracted twicewith ethyl acetate. The combined organic layer was washed with brine,dried over sodium sulfate, filtered and concentrated under reducedpressure. The residue was crystallized from ethyl acetate-diethyl etherto obtain the title compound (112 mg, yield: 34%).

[3865] Melting point: 114-116° C.

[3866]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.33 (6H, s), 2.30 (2H, s),2.45-2.60 (2H, m), 2.70 (2H, s), 3.38 (2H, t, J=7.5 Hz), 3.81 (2H, t,J=6.6 Hz), 3.92 (3H, s), 6.60 (1H, s), 7.24-7.27 (2H, m), 7.39-7.42 (2H,m).

Example 518

[3867]N,N-Dimethyl-N′-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]sulfamide

[3868] Triethylamine (0.15 mL, 1.07 mol) and dimethylsulfamoyl chloride(0.10 mL, 0.970 mmol) were added to a solution of3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquiinolin-1-yl)benzenamine(340 mg, 0.970 mmol) in tetrahydrofuran (3 mL) with cooling in ice, andthe mixture was heated under reflux for 15 hours. Water was poured intothe reaction mixture, which was made basic by adding 1 M aqueoussolution of sodium hydroxide, and extracted twice with ethyl acetate.The combined organic layer was washed with a brine, dried over magnesiumsulfate, filtered, and concentrated under reduced pressure. The residuewas subjected to a column chromatography on a basic silica gel(hexane/ethyl acetate 1:2), and crystallized from diethyl ether toobtain the title compound (226 mg, yield: 51%).

[3869] Melting point: 134-136° C.

[3870]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.32 (6H, s), 2.24 (2H, s), 2.70(2H, s), 2.82 (6H, s), 3.92 (3H, s), 6.61 (1H, s), 7.09-7.13 (2H, m),7.21-7.36 (2H, m).

Example 519

[3871]N-[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2-propenamide

[3872] Triethylamine (0.47 mL, 3.36 mmol) and 3-chloropropionyl chloride(0.31 mL, 3.21 mmol) were added to a solution of3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine(1.07 g, 3.05 mmol) in tetrahydrofuran (10 mL) with cooling in ice, andthe mixture was stirred at the same temperature for 1.5 hours. Ice waterwas poured to the reaction mixture, which was extracted three times withethyl acetate. The combined organic layer was washed with brine, driedover sodium sulfate, filtered and concentrated under reduced pressure.The residue was subjected to a column chromatography on a silica gel(hexane/ethyl acetate 1:1 followed by hexane/ethyl acetate/methanol25:25:1), crystallized from diethyl ether-hexane to obtain ca. 1:1mixture (1.12 g) of the title compound and3-chloro-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]propanamide.

[3873] Potassium carbonate (220 mg, 1.59 mmol) and potassium iodide (22mg, 0.133 mmol) were added to a solution of this substance inN,N-dimethylformamide (10 mL) and the mixture was stirred at 60° C. for4 hours. Water was poured into the reaction mixture, which was extractedtwice with ethyl acetate. The combined organic layer was washed withwater and brine, dried over sodium sulfate, filtered and concentratedunder reduced pressure. The residue was subjected to a columnchromatography on a basic silica gel (hexane/ethyl acetate 3:1),crystallized from diethyl ether-diisopropyl ether to obtain the titlecompound (419 mg, yield: 34%).

[3874] Melting point: 188-190° C.

[3875]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.32 (6H, s), 2.30 (2H, s), 2.68(2H, s), 3.92 (3H, s), 5.74 (1H, dd, J=10.0, 1.6 Hz), 6.22 (1H, dd,J=16.9, 10.0 Hz), 6.41 (1H, dd, J=16.9, 1.6 Hz), 6.60 (1H, s), 7.07 (1H,d, J=8.0 Hz), 7.31 (1H, t, J=8.0 Hz), 7.44 (1H, s), 7.77 (1H, d, J=8.0Hz), 7.96 (1H, s).

Example 520

[3876]4-Chloro-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]butanamide

[3877] Triethylamine (0.81 mL, 5.81 mmol) and 4-chlorobutyryl chloride(0.62 mL, 5.54 mmol) were added to a solution of3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine(1.85 g, 5.28 mmol) in tetrahydrofuran (15 mL) with cooling in ice, andthe mixture was stirred at the same temperature for 1 hour. Ice waterand an aqueous solution of sodium hydroxide were poured into thereaction mixture, which was extracted with ethyl acetate. The organiclayer was washed with brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was crystallized fromdiethyl ether-diisopropyl ether to obtain the title compound (2.25 g,yield: 94%).

[3878] Melting point: 146-148° C.

[3879]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.32 (6H, s), 2.10-2.23 (2H, m),2.30 (2H, s), 2.52 (2H, t, J=7.1 Hz), 2.69 (2H, s), 3.65 (2H, t, J=6.0Hz), 3.92 (3H, s), 6.60 (1H, s), 7.07 (1H, d, J=7.6 Hz), 7.31 (1H, t,J=7.6 Hz), 7.45 (1H, s), 7.77 (1H, d, J=7.6 Hz), 7.78 (1H, s).

Example 521

[3880]1-[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2-pyrrolidinonehydrochloride

[3881] Potassium carbonate (514 mg, 3.72 mmol) and potassium iodide (56mg, 0.338 mmol) were added to a solution of4-chloro-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]butanamide(1.54 g, 3.38 mmol) in N,N-dimethylformamide (10 mL) and the mixture wasstirred at 60° C. for 2 hours and 80° C. for 5 hours. Water was pouredinto the reaction mixture, which was extracted twice with ethyl acetate.The combined organic layer was washed with water and brine, dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresidue was subjected to a column chromatography on a silica gel (ethylacetate followed by ethyl acetate/triethylamine 50:1) to obtain a freebase of the title compound. This was dissolved in ethyl acetate,combined with 4 M hydrogen chloride/ethyl acetate solution, concentratedunder reduced pressure, triturated with diethyl ether to obtain thetitle compound (941 mg, yield: 61%).

[3882] Amorphous.

[3883]¹H MMR (DMSO-d₆) δ1.23 (6H, s), 1.44 (6H, s), 2.02-2.15 (2H, m),2.20-2.40 (2H, m), 2.45-2.60 (2H, m), 3.14 (2H, s), 3.70-4.05 (2H, m),3.94 (3H, s), 7.09 (1H, s), 7.35 (1H, d, J=8.0 Hz), 7.60-7.68 (1H, m),7.90 (1H, s), 7.94 (1H, d, J=8.0 Hz).

Example 522

[3884]3-Chloro-2,2-dimethyl-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]propanamide

[3885] Triethylamine (1.30 mL, 9.30 mmol) and 3-chloropivaloyl chloride(1.15 mL, 8.87 mmol) were added to a solution of3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine(2.96 g, 8.45 mmol) in tetrahydrofuran (20 mL) with cooling in ice, andthe mixture was stirred at room temperature for 30 minutes. Ice waterwas poured into the reaction mixture, which was extracted twice withethyl acetate. The combined organic layer was washed with a brine, driedover sodium sulfate, filtered and concentrated under reduced pressure.The residue was crystallized from ethyl acetate-hexane to obtain thetitle compound (3.83 g, yield: 97%).

[3886] Melting point: 189-191° C.

[3887]¹H NMR (CDCl₃) δ1.24 (6H, s), 1.32 (6H, s), 1.42 (6H, s), 2.31(2H, s), 2.68 (2H, s), 3.70 (2H, s), 3.92 (3H, s), 6.61 (1H, s), 7.12(1H, dd, J=7.6, 1.4 Hz), 7.35 (1H, t, J=7.6 Hz), 7.48 (1H, t, J=1.4 Hz),7.55 (1H, br s), 7.81 (1H, dd, J=7.6, 1.4 Hz).

Example 523

[3888]3,3-Dimethyl-1-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2-azethidinonehydrochloride

[3889] Potassium carbonate (529 mg, 3.83 mmol) and potassium iodide (58mg, 0.348 mmol) were added to absolution of3-chloro-2,2-dimethyl-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]propanamide(1.63 g, 3.48 mmol) in N,N-dimethylformamide (15 mL).and the mixture wasstirred at 70° C. for 3 hours. Ice water was added to the reactionmixture, which was extracted twice with ethyl acetate. The combinedorganic layer was washed with brine, dried over sodium sulfate, filteredand concentrated under reduced pressure. The residue was subjected to acolumn chromatography on a basic silica gel (hexane/ethyl acetate 5:1followed by 3:1) to obtain a free base of the title compound. This wasdissolved in ethyl acetate, combined with 4 M hydrogen chloride/ethylacetate solution, concentrated under reduced pressure, crystallized fromethyl acetate-diisopropyl ether to obtain the title compound (1.50 g,yield: 92%).

[3890] Melting point: 191-193° C.

[3891]¹H NMR (DMSO-₆) δ1.24 (6H, s), 1.32 (6H, s), 1.44 (6H, s), 2.29(2H, s), 3.14 (2H, s), 3.58 (2H, s), 3.94 (3H, s), 7.09 (1H, s),7.29-7.31 (1H, m), 7.62-7.64 (3H, m).

Example 524

[3892]5-Oxo-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2-pyrrolidinecarboxamide

[3893] Thionyl chloride (2.06 mL, 28.3 mmol) and N,N -dimethylfonmamide(1 drop) were added to a solution of D,L-pyroglutamic acid (3.65 g, 28.3mmol) in toluene (16 mL) and the mixture was stirred at 50° C. for 40minutes. After distilling the solvent off under reduced pressure, theresidue was dissolved in N,N-dimethylformamide (10 mL) and3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine(1.98 g, 5.66 mmol) and triethylamine (3.94 mL, 28.3 mmol) were addedthereto, and the mixture was stirred at room temperature for 3 hours. Anaqueous solution of sodium chloride was poured into the reactionmixture, which was extracted twice with ethyl acetate-tetrahydrofuran.The combined organic layer was washed with brine, dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas subjected to a column chromatography on a basic silica gel (ethylacetate followed by ethyl acetate/methanol 30:1), and crystallized fromethyl acetate-hexane to obtain the title compound (1.57 g, yield: 60%).

[3894] Melting point: 145-147° C.

[3895]¹H NMR (CDCl₃) δ1.23 (6H, s), 1.31 (6H, s), 2.27 (2H, s),2.30-2.59 (4H, m), 2.67 (2H, s), 3.92 (3H, s), 4.20-4.30 (1H, m), 6.60(1H, s), 6.94 (1H, s), 7.09 (1H, d, J=8.0 Hz), 7.23-7.37 (1H, m), 7.53(1H, s), 7.74 (1H, d, J=8.0 Hz), 8.50 (1H, s).

Example 525

[3896]N-Methyl-5-oxo-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2-pyrrolidinecarboxamidehydrochloride

[3897] Thionyl chloride (0.51 mL, 7.04 mmol) and N,N-dimethylformamide(1 drop) were added to a solution of D,L-pyroglutamic acid ( 909 mg,7.04 mmol) in toluene (4 mL) and the mixture was stirred at 50° C. for40 minutes. After distilling the solvent off, the residue was dissolvedin N,N-dimethylformamide (4 mL ), andN-methyl-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine(493 mg, 1.35 mmol) and triethylamine (0.98 mL, 7.04 mmol) were addedthereto with cooling in ice, and the mixture was stirred at roomtemperature for 3 hours. Brine was poured into the reaction mixture,which was extracted three times with ethyl acetate-tetrahydrofuran. Thecombined organic layer was washed with brine, dried over sodium sulfate,filtered and concentrated under reduced pressure. The residue wassubjected to a column chromatography on a basic silica gel (ethylacetate) to obtain a free base of the title compound. This was dissolvedin ethyl acetate, combined with 4 M hydrogen chloride/ethyl acetatesolution, concentrated under reduced pressure, triturated with di ethylether to obtain the title compound (516 mg, yield: 75%).

[3898] Amorphous.

[3899]¹H NMR (DMSO-d₆) δ1.23 (6H, s), 1.47 (6H, s), 1.90-2.30 (4H, m),2.19 (2H, s), 3.17 (2H, s), 3.25 (3H, s), 3.94 (3H, s), 4.00-4.15 (1H,m), 7.11 (1H, s), 7.55-7.85 (5H, m).

Example 526

[3900]2,6-Dichloro-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-3-pyridinecarboxamide

[3901] N,N′-Carbonyldiimidazole (160 mg, 0.989 mmol) was added to asolution of 2,6-dichloronicotinic acid (90%) (188 mg, 0.881 mmol) inN,N-dimethylformamide (2.5 mL) and the mixture was stirred at roomtemperature for 1 hour. 3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,88-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine (347 mg, 0.989mmol) was added to the mixture, and the mixture was stirred at roomtemperature for 1 hour and at 60° C. for 2 hours and 90° C. for 15hours. Water was poured into the reaction mixture, which was extractedtwice with ethyl acetate-tetrahydrofuran. The combined organic layer waswashed with water and brine dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was subjected to acolumn chromatography on a basic silica gel (hexane/ethyl acetate 2:1followed by 1:1), crystallized from ethyl acetate-hexane to obtain thetitle compound (95 mg, yield: 18).

[3902] Melting point; 130-132° C.

[3903]¹H NMR (CDCl₃) δ1.23 (6H, s), 1.34 (6H, br s), 2.33 (2H, s), 2.69(2H, s), 3.93 (3H, s), 6.61 (1H, s), 7.19 (1H, d, J=7.5 Hz), 7.37-7.43(2H, m), 7.61 (1H, s), 7.84 (1H, d, J=7.5 Hz), 8.13 (1H, d, J=8.0 Hz),8.56 (1H, s).

Example 527

[3904]N-[3-[[[[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]amino]carbonyl]amino]phenyl]acetamidehydrochloride

[3905] N,N′-Carbonyldiimidazole (151 mg, 0.933 mmol) was added to asolution of3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine(327 mg, 0.933 mmol) in N,N-dimethylformamide (3 mL) and the mixture wasstirred at room temperature for 1 hour. 3′-Aminoacetanilide (140 mg,0.933 mmol) was added to the mixture and the mixture was stirred at roomtemperature for 3 hours. Ice water was poured into the reaction mixture,which was extracted three times with ethyl acetate. The combined organiclayer was concentrated under reduced pressure. The residue was subjectedto a column chromatography on a basic silica gel (hexane/ethyl acetate1:2, ethyl acetate followed by ethyl acetate/methanol 20:1) to obtain afree base of the title compound. This was dissolved in ethyl acetate,combined with 4 M hydrogen chloride/ethyl acetate solution, concentratedunder reduced pressure, triturated with diethyl ether to obtain thetitle compound (128 mg, yield: 24%).

[3906] Amorphous.

[3907]¹H NMR (DMSO-d₆) δ1.24 (6H, s), 1.44 (6H, s), 2.02 (3H, s),2.18-2.55 (2H, m), 3.15 (2H, br s), 3.94 (3H, s), 7.09 (1H, s),7.13-7.23 (4H, m), 7.50-7.88 (4H, m), 9.30 (1H, s), 9.59 (1H, s), 9.93(1H, s).

Example 528

[3908][3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]urea

[3909] Sodium cyanate (121 mg, 1.87 mmol) and trifluoroacetic acid(0.36mL, 4.67 mmol) were added to a solution of3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine(327 mg, 0.933 mmol) in tetrahydrofuran (3 mL) with cooling in ice, andthe mixture was stirred at room temperature for 1 hour. The reactionmixture was neutralized with 1 M aqueous solution of sodium hydroxide,and extracted twice with ethyl acetate. The combined organic layer waswashed with a brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was subjected to acolumn chromatography on a basic silica gel (ethyl acetate),crystallized from diisopropyl ether to obtain the title compound (303mg, yield: 83%).

[3910] Melting point: 174-176° C.

[3911]¹H NMR (CDCl₃) δ1.23 (6H, s), 1.32 (6H, s), 2.28 (2H, s), 2.70(2H, s), 3.93 (3H, s), 4.89 (2H, br s), 6.60 (1H, s), 6.98 (1H, d, J=7.6Hz), 7.25-7.33 (2H, m), 7.49 (1H, d, J=8.2 Hz), 7.55 (1H, s).

Example 529

[3912]N-Methyl-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]urea

[3913] Sodium cyanate (125 mg, 1.92 mmol) and trifluoroacetic acid (0.37mL, 4.80 mmol) were added to a solution ofN-methyl-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine(350 mg, 0.960 mmol) in tetrahydrofuran (3 mL) with cooling in ice, andstirred at room temperature for 1 hour. The reaction mixture wasneutralized with 1 M aqueous solution of sodium hydroxide, and extractedtwice with ethyl acetate. The combined organic layer was washed with abrine, dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was subjected to a column chromatographyon a basic silica gel (hexane/ethyl acetate 1:2), crystallized fromethyl acetate-hexane to obtain the title compound (263 mg, yield: 67%).

[3914] Melting point: 108-109° C.

[3915]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.33 (6H, s), 2.22 (2H, s), 2.70(2H, s), 3.28 (3H, s), 3.93 (3H, s), 4.42 (2H, br s), 6.62 (1H, s),7.30-7.52 (4H, m).

Example 530

[3916]N-Methyl-N′-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]urea

[3917] Phenyl chlorocarbonate (0.11 mL, 0.902 mmol) and triethylamine(0.13 mL, 0.902 mmol) were added to a solution of3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine(316 mg, 0.902 mmol) in N,N-dimethylformamide (3 mL) and the mixture wasstirred at room temperature for 1 hour. Methylamine hydrochloride (73mg, 1.08 mmol) and triethylamine (0.31 mL, 2.26 mmol) were added to themixture, and the mixture was stirred at room temperature for 2 hours andat 50° C. for 5 hours. Water was added to the reaction mixture, whichwas extracted three times with ethyl acetate. The combined organic layerwas washed with brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was subjected to acolumn chromatography on a basic silica gel (ethyl acetate followed byethyl acetate/methanol 50:1), crystallized from ethylacetate-diisopropyl ether to obtain the title compound (278 mg, yield:76%).

[3918] Melting point: 125-127° C.

[3919]¹H NMR (CDCl₃) δ1.24 (6H, s), 1.31 (6H, s), 2.29 (2H, s), 2.69(2H, s), 2.74 (3H, d, J=4.4 Hz), 3.92 (3H, s), 5.13 (1H, br s), 6.60(1H, s), 6.95 (1H, d, J=7.6 Hz), 7.02 (1H, s), 7.21-7.39 (2H, m).

Example 531

[3920]N-(2-Pyridinyl)-N′-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]urea

[3921] Triethylamine (0.13 mL, 0.899 mmol) and phenyl chlorocarbonate(0.11 mL, 0.899 mmol) were added to a solution of3-(3,4,8,9-tetranydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine(315 mg, 0.899 mmol) in N,N-dimethylformamide (3 mL) with cooling inice, and the mixture was stirred at room temperature for 40 minutes.2-Aminopyridine (93 mg, 0.989 mmol) was added to the mixture and themixture was stirred at room temperature for 2 hours and at 60° C. for 2hours. Ice water was poured into the reaction mixture, which wasextracted twice with ethyl acetate. The combined organic layer waswashed with water and brine, and concentrated under reduced pressure.The residue was subjected to a column chromatography on a basic silicagel (hexane/ethyl acetate 1:1 followed by 1:2), crystallized fromdiisopropyl ether to obtain the title compound (166 mg, yield: 39%).

[3922] Melting point: 189-191° C.

[3923]¹H NMR (CDCl₃) δ1.27 (6H, s), 1.32 (6H, s), 2.35 (2H, s), 2.71(2H, s), 3.93 (3H, s), 6.62 (1H, s), 6.81 (1H, d, J=8.0 Hz), 6.91-6.97(1H, m), 7.09 (1H, d, J=7.6 Hz), 7.36 (1H, t, J=8.0 Hz), 7.56-7.66 (2H,m), 7.81 (1H, d, J=7.6 Hz), 8.25-8.28 (2H, m), 11.91 (1H, s).

Example 532

[3924]N-(2-Chloroethyl)-N′-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]urea

[3925] 2-Chloroethyl isocyanate (0.12 mL, 1.48 mmol) was added to asolution of3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine(519 mg, 1.48 mmol) in N,N-dimethylformamide (5 mL) and the mixture wasstirred at room temperature for 3 hours. An aqueous solution of sodiumchloride was poured into the reaction mixture, which was extracted threetimes with ethyl acetate. The combined organic layer was washed withbrine, dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was subjected to a column chromatographyon a basic silica gel (hexane/ethyl acetate 1:1 followed by ethylacetate), crystallized from diethyl ether to obtain the title compound(477 mg, yield: 71%).

[3926] Melting point: 147-150° C.

[3927]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.32 (6H, s), 2.30 (2H, s), 2.71(2H, s), 3.45-3.63 (4H, m), 3.92 (3H, s), 5.68 (1H, t, J=5.2 Hz), 6.60(1H, s), 6.95 (1H, d, J=7.8 Hz), 7.20 (1H, s), 7.24 (1H, t, J=7.8 Hz),7.42 (1H, d, J=7.8 Hz), 7.59 (1H, s).

Example 533

[3928]1-[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2-imidazolidinone

[3929] Potassium tert-butoxide (86 mg, 0.770 mmol) was added to asolution ofN-(2-chloroethyl)-N′-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]urea(351 mg, 0.770 mmol) in N,N-dimethylformamide (3 mL) with cooling inice, and the mixture was stirred at room temperature for 4 hours. Waterwas poured into the reaction mixture, which was extracted twice withethyl acetate. The combined organic layer was washed with brine, driedover sodium sulfate, filtered and concentrated under reduced pressure.The resultant crystals were washed with diisopropyl ether to obtain thetitle compound (251 mg, yield: 78%).

[3930] Melting point: 225-227° C.

[3931]¹H NMR (CDCl₃) δ1.24 (6H, s), 1.32 (6H, s), 2.30 (2H, br s), 2.68(2H, s), 3.57 (2H, t, J=8.1 Hz), 3.92 (3H, s), 3.99 (2H, t, J=8.1 Hz),4.60 (1H, s), 6.60 (1H, s), 7.05 (1H, d, J=7.8 Hz), 7.35 (1H, t, J=7.8Hz), 7.35 (1H, s), 7.80 (1H, d, J=7.8 Hz).

Example 534

[3932]N,N′-Dimethyl-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]sulfamidehydrochloride

[3933] Chlorosulfonyl isocyanate (0.14 mL, 1.57 mmol) was added to asolution of 2-methyl-2-propanol (0.15 mL, 1.57 mmol) in tetrahydrofuran(3 mL) with cooling in ice and the mixture was stirred at roomtemperature for 30 minutes. With cooling in ice,3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine(500 mg, 1.43 mmol) and triethylamine (0.24 mL, 1.72 mmol) were added tothe mixture and the mixture was stirred at room temperature for 2 hours.Ice water was poured into the reaction mixture, which was extractedthree times with ethyl acetate-tetrahydrofuran. The combined organiclayer was washed with brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was subjected to acolumn chromatography on a silica gel (hexane/ethyl acetate 2:1 followedby 1:1) to obtain[[[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]amino]sulfonyl]carbamicacid 1,1-dimethylethyl ester (510 mg, yield: 67%) as crystals.

[3934]¹H NMR (CDCl₃) δ1.27 (6H, s), 1.33 (6H, s), 1.41 (9H, s), 2.22(2H, s), 2.71 (2H, s), 3.93 (3H, s), 6.62 (1H, s), 7.21-7.41 (4H, m).

[3935] Sodium hydride (66% dispersion in oil) (36 mg, 0.991 mmol) wasadded to a solution of the resultant carbamic acid derivative (500 mg,0.944 mmol) in N,N-dimethylformamide (5 mL) with cooling in ice, and themixture was stirred at room temperature for 30 minutes. With cooling inice, iodomethane (0.06 mL, 0.991 mmol) was added to the mixture and themixture was stirred at room temperature for 3 hours.

[3936] Water was poured into the reaction mixture, and extracted twicewith ethyl acetate. The combined organic layer was washed with water andbrine, dried over'sodium sulfate, filtered and concentrated underreduced pressure. The residue was subjected to a column chromatographyon a silica gel (hexane/ethyl acetate 2:1) to obtain an about 1:1mixture of(methyl)[[[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]amino]sulfonyl]carbamicacid 1,1-dimethylethyl ester and(methyl)[[(methyl)[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]amino]sulfonyl]carbamicacid 1,1-dimethylethyl ester (379 mg).

[3937] 4 M hydrogen chloride/ethyl acetate solution (3 mL) was added tothe,resultant mixture (370 mg) and the mixture was stirred at roomtemperature for 1 hour. Water was poured into the reaction mixture,which was neutralized with 5 M aqueous solution of sodium hydroxide, andthen extracted with ethyl acetate. The organic layer was washed with abrine, dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was subjected to a column chromatography,on a basic silica gel (hexane/ethyl acetate 1:1) to obtain a free baseof the title compound. This was dissolved in ethyl acetate, combinedwith 4 M hydrogen chloride/ethyl acetate solution, concentrated underreduced pressure, triturated with diethyl ether to obtain the titlecompound (129 mg, yield: 28%).

[3938] Amorphous.

[3939]¹H NMR (DMSO-d₆) δ1.19 (6H, s), 1.40 (3H, s), 1.45 (3H, s),1.97-2.50 (2H, m), 2.51 (3H, d, J=4.8 Hz), 3.14 (2H, s), 3.15 (3H, s),3.91 (3H, s), 7.06 (1H, s), 7.43-7.67 (4H, m).

Example 535

[3940]N-Methyl-N′-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]sulfamide

[3941] After separating N,N′-dimethyl form in the column chromatographyin Example 534, followed by elution with hexane/ethyl acetate 1:2followed by crystallization from diethyl ether, the title compound wasobtained (85 mg, yield: 21%).

[3942] Melting point: 135-136° C.

[3943]¹H NMR (CDCl₃) δ1.28 (6H, s), 1.33 (6H, br s), 2.25 (2H, s), 2.60(3H, s), 2.72 (2H, s), 3.93 (3H, s), 5.86 (1H, br s), 6.62 (1H, s),7.03-7.14 (2H, m), 728-7.39 (2H, m).

Example 536

[3944]N-[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]sulfamidehydrochloride

[3945] 4 M hydrogen chloride/ethyl acetate solution (3 mL) was added to[[[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]amino]sulfonyl]carbamicacid 1,1-dimethylethyl ester (539 mg, 1.02 mmol) and the mixture wasstirred at room temperature for 3 hours. The reaction mixture wasneutralized with 5 M aqueous solution of sodium hydroxide, and extractedwith ethyl acetate. The organic layer was washed with brine, dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresidue was subjected to a column chromatography on a basic silica gel(hexane/ethyl acetate 1:1 followed by ethyl acetate) to obtain a freebase Of the title compound. This was dissolved in ethyl acetate,combined with 4 M hydrogen chloride/ethyl acetate solution, concentratedunder reduced pressure, and crystallized from ethanol-diusopropyl etherto obtain the title compound (333 mg, yield: 70%)

[3946] Melting point: 191-194° C.

[3947]¹H NMR (DMSO-d₆) δ1.22 (6H, s), 1.41 (3H, s), 1.47 (3H, s),2.00-2.55 (2H, m), 3.00-3.40 (2H, m), 3.94 (3H, s), 7.09 (1H, s),7.18-7.59 (6H, m), 9.99 (1H, s).

Example 537 5-[3-(3,4,8,9-Tetrahydro6methoxy3,3,8,8tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-1,2,5-thiadiazolidine-2-carboxylate1,1 -dimethylethyl ester 1,1-dioxide

[3948] Sodium hydride (66% dispersion in oil) (45 mg, 1.24 mmol) wasadded to a solution of[[[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]amino]sulfonyl]carbamicacid 1,1-dimethylethyl ester (312 mg, 0.589 mmol) inN,N-dimethylformamide (3 mL) and the mixture was stirred at roomtemperature for 30 minutes. With cooling in ice, 1,2-dibromoethane(0.051 mL, 0.589 mmol) was added to the mixture and the mixture wasstirred at room temperature for 3.5 hours. Water was poured into thereaction mixture, which was extracted twice with ethyl acetate. Thecombined organic layer was washed with water and a brine, dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresidue was subjected to a column chromatography on a basic silica gel(hexane/ethyl acetate 3:1 followed by 2:1, recrystallized fromdiisopropyl ether to obtain the title compound (133 mg, yield: 41%).

[3949] Melting point: 157-159° C.

[3950]¹H NMR (CDCl₃) δ1.24 (6H, s), 1.32 (6H, s), 1.56 (9H, s), 2.26(2H, br s), 2.69 (2H, s), 3.78-3.85 (2H, m), 3.92 (3H, s), 3.92-3.99(2H, m), 6.60 (1H, s), 7.32-7.36 (2H, m), 7.44-7.46 (2H, m).

Example 538

[3951]2-[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-1,2,5-thiadiazolidine1,1-dioxlde

[3952] 4 M hydrogen chloride/ethyl acetate solution (10 mL) was added to5-[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-1,2,5-thiadiazolidine-2-carboxylicacid 1,1-dimethylethyl ester 1,1-dioxide (1.30 g, 2.34 mmol) and themixture was stirred at room temperature for 2 hours. The reactionmixture was neutralized with 2 M aqueous solution of sodium hydroxide,and extracted twice with ethyl acetate. The combined organic layer waswashed with a brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure. The crystals of the residue werewashed with diisopropyl ether to obtain the title compound (922 mg,yield: 87%).

[3953] Melting point: 145-147° C.

[3954]¹H NMR (CDCl₃) δ1.32 (12H, s), 2.22 (2H, s), 2.72 (2H, s), 3.18(2H, br s), 3.64-3.80 (2H, br), 3.93 (3H, s), 6.61 (1H, s), 7.04-7.07(2H, m), 7.39 (1H, t, J=7.6 Hz), 7.59 (1H, d, J=7.6 Hz).

Example 539

[3955][5-[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-1,2,5-thiadiazolidine-2-acetamide1,1-dioxide

[3956] Potassium tert-butoxide (77 mg, 0.687 mmol) was added to asolution of2-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-1,2,5-thiadiazolidine1,1-dioxide (313 mg, 0.687 mmol) in N,N-dimethylformamide (3 mL) and themixture was stirred at room temperature for 30 minutes. 2-Bromoacetamide(95 mg, 0.687 mmol) was added to the mixture and the mixture was stirredat room temperature for 2 hours, and 2-bromoacetamide (95 mg, 0.687mmol) was further added and the mixture was stirred at room temperaturefor 1 hour. Water was poured into the reaction mixture, which wasextracted three times with ethyl acetate. The combined organic layer waswashed with brine, dried over sodium sulfate, filtered and concentratedunder reduced pressure. The residue was subjected to a columnchromatography on a basic silica gel (ethyl acetate, ethylacetate/triethylamine 50:1 followed by ethylacetate/methanol/triethylamine 50:1:1), crystallized from ethylacetate-diisopropyl ether to obtain the title compound (206 mg, yield:59%).

[3957] Melting point: 206-208° C.

[3958]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.32 (6H, s), 2.26 (2H, br s), 2.69(2H, s), 3.65 (2H, t, J=6.6 Hz), 3.85 (2H, s), 3.92 (2H, t, J=6.6 Hz),3.92 (3H, s), 5.63 (1H, br s), 6.61 (1H, s), 6.62 (1H, br s), 7.26-7.30(2H, m), 7.38-7.45 (2H, m).

Example 540

[3959]5-[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-1,2,5-thiadiazolidine-2-acetlcacid ethyl ester 1,1-dioxide

[3960] Potassium tert butoxide (695 mg, 6.19 mmol) was added to asolution of2-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-1,2,5-thiadiazolidine1,1-dioxide (1.88 g, 4.13 mmol) in N,N-dimethylformamide (15 mL) and themixture was stirred at room temperature for 30 minutes. Ethylbromoacetate (0.46 mL, 4.13 mmol) was added to the mixture, and themixture was stirred at room temperature for 1 hour. Water was pouredinto the reaction mixture, which was extracted three times with ethylacetate. The combined organic layer was washed with brine, dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresidue was subjected to a column chromatography on a basic silica gel(hexane/ethyl acetate 3:1 followed by 1:1), crystallized from diethylether to obtain the title compound (583 mg, yield: 26%).

[3961] Melting point: 153-155° C.

[3962]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.31 (3H, t, J=7.0 Hz), 1.32 (6H,s), 2.27 (2H, s), 2.69 (2H, s), 3.73 (2H, t, J=6.2 Hz), 3.92 (2H, t,J=6.2 Hz), 3.92 (5H, s), 4.25 (2H, q, J=7.0 Hz), 6.60 (1H, s), 7.23-7.27(2H, m), 7.41-7.43 (2H, m).

Example 541

[3963]2-[(2-Oxo-3-pyrrolidinyl)amino]-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]acetamidedihydrochloride

[3964] D,L-3-Amino-2-pyrrolidinone (83 mg, 0.825 mmol), potassiumcarbonate (114 mg, 0.825 mmol) and potassium iodide (13 mg, 0.0750 mmol)were added to a solution of2-chloro-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]acetamide(320 mg, 0.750 mmol) in N,N-dimethylformamide (3 mL) and the mixture wasstirred at 60° C. for 1 hour. An aqueous solution of sodium chloride waspoured into the reaction mixture, which was extracted twice with ethylacetate-tetrahydrofuran. The combined organic layer was washed withbrine, dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was subjected to a column chromatographyon a basic silica gel (ethyl acetate/methanol 10:1 followed by ethylacetate/methanol/triethylamine 50:5:1) to obtain a free base of thetitle compound. This was dissolved in ethyl acetate, combined with 4 Mhydrogen chloride/ethyl acetate solution, concentrated under reducedpressure, crystallized from ethanol-ethyl acetate-dulsopropyl ether toobtain the title compound (245 mg, yield: 58%).

[3965] Melting point: 181-184° C.

[3966]¹H NMR (DMSO-d₆) δ1.24 (6H, s), 1.44 (6H, s), 2.10-2.42 (4H, m),3.16-3.30 (4H, m), 3.94 (3H, s), 4.01-4.33 (3H, m), 7.10 (1H, s), 7.37(1H, d, J=8.0 Hz), 7.65 (1H, t, J=8.0 Hz), 7.86 (1H, s), 7.87 (1H, d,J=8.0 Hz), 8.40 (1H, s), 9.40-10.00 (2H, m), 11.32 (1H, s).

Example 542

[3967]2-[Acetyl(2-oxo-3-pyrrolidinyl)amino]-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]acetamidehydrochloride

[3968] D,L-3-Amino-2-pyrrolidinone (87 mg, 0.871 mmol), potassiumcarbonate (120 mg, 0.871 mmol) and potassium iodide (13 mg, 0.0792 mmol)were added to a solution of2-chloro-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]acetamlde(338 mg, 0.792 mmol) in N,N-dimethylformamide (3 mL) and the mixture wasstirred at 60° C. for 2.5 hours. With cooling in ice, acetyl chloride(0.12 mL, 0.174 mmol) and triethylamine (0.36 mL, 2.61 mmol) were addedto the mixture, and the mixture was stirred at room temperature for 2hours. Water was poured into the reaction mixture, which was extractedtwice with ethyl acetate. The combined organic layer was washed withbrine, dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was subjected to a column chromatographyon a basic silica gel (ethyl acetate/methanol 50:1 followed by 10:1) toobtain a free base of the title compound This was dissolved in ethylacetate, combined with 4 M hydrogen chloride/ethyl acetate solution,concentrated under reduced pressure, crystallized fromethanol-diisopropyl ether to obtain the title compound (167 mgyield:37%).

[3969] Melting point: 197-200° C.

[3970]¹H NMR (DMSO-d₆) δ1.22 (6H, s), 1.42 (6H, s), 1.96 (3H, s),2.05-2.33 (4H, m), 3.10-3.58 (4H, m), 3.94 (3H, s), 4.15-4.81 (3H, m),7.10 (1H, s), 7.29 (0.5H, d, J=7.6 Hz), 7.35 (0.5H, d, J=7.6 Hz),7.55-7.67 (1H, m), 7.70-8.05 (1H, m), 7.98 (1H, s), 8.12 (0.5H, s), 8.19(0.5H, s), 10.49 (0.5H, s), 11.23 (0.5H, s).

Example 543

[3971]2-[Methyl(2-oxo-3-pyrrolidinyl)amino]-N-[3-(3,4,8,9-tetrahydro-6-mrethoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]acetamide

[3972] Potassium carbonate (89 mg, 0.645 mmol) and iodomethane (0.021mL, 0.338 mmol) were added to a solution of2-[(2-oxo-3-pyrrolidinyl)amino]-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]acetamidedihydrochloride (173 mg, 0.307 mmol) in N,N-dimethylformamide (1.5 mL)with cooling in ice, and the mixture was stirred at room temperature for2 hours. Brine was poured into the reaction mixture, which was extractedtwice with ethyl acetate-tetrahydrofuran. The combined organic layer waswashed with brine, dried over sodium sulfate, filtered and concentratedunder reduced pressure. The residue was subjected to a columnchromatography on a basic silica gel (hexane/ethyl acetate/triethylamine30:1:1), crystallized from ethyl acetate-diethyl ether to obtain thetitle compound (4-mg, yield: 3%).

[3973] Melting point: 112-114° C.

[3974]¹H NMR (CDCl₃) δ1.23 (3H, s), 1.27 (3H, s), 1.32 (6H, s),2.05-2.45 (2H, m), 2.30 (2H, s), 2.50 (3H, s), 2.68 (2H, s), 3.29 (2H,s), 3.32-3.42 (2H, m), 3.55-3.64 (1H, m), 3.92 (3H, s), 5.64 (1H, s),6.60 (1H, s), 7.07 (1H, d, J=3 8.0 Hz), 7.34 (1H, t, J=8.0 Hz), 7.54(1H, s), 7.89 (1H, d, J=8.0 Hz), 9.67 (1H, s).

Example 544

[3975]3-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid ethyl ester

[3976] A solution of ethyl 3-cyanobenzoate (27.6 g, 157 mmol) in aceticacid (90 mL)-toluene (150 mL) was treated dropwise with conc. sulfuricacid (17.6 mL, 330 mmol) with cooling in ice, and1-(7-ethoxy-2,3-dihydro-2,2-dimethyl-5-benzofuranyl)-2-methyl-1-propanol(50.0 g, 189 mmol) was added thereto at room temperature, and themixture was stirred at 65° C. for 1 hour. Ethanol (105 mL) was addeddropwise to the mixture and the mixture was stirred at 75° C. for 40minutes. Water was poured into the reaction mixture, and the organicphase was separated and extracted with 2 M hydrochloric acid. Thecombined aqueous layer was neutralized with conc. aqueous ammonia, andextracted twice with ethyl acetate (I). The combined organic layer waswashed with 0.5 M aqueous solution of sodium hydroxide (II). water andbrine, dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was crystallized from hexane to obtain thetitle compound (11.8 g, yield: 18%).

[3977] Melting-point: 97-100° C.

[3978]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.30 (6H, s), 1.39 (3H, t, J=7.1Hz), 1.47 (3H, t, J=7.1 Hz), 2.15 (2H, s), 2.68 (2H, s), 4.19 (2H, q,J=7.1 Hz), 4.38 (2H, q, J=7.1 Hz), 6.62 (1H, s), 7.47 (1H, ddd, J=7.5,7.4, 1.2 Hz), 7.61 (1H, ddd, J=7.4, 1.8, 1.2 Hz), 8.06-8.10 (2H, m).

Example 545

[3979]3-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid

[3980] The aqueous layers in EXAMPLE 544 ((I) and (II)) were combined,neutralized with 5 M hydrochloric acid, and extracted three times withethyl acetate-tetrahydrofuran. The combined organic layer wasconcentrated under reduced pressure, crystallized from ethyl acetate toobtain the title compound (2.77 g, yield: 5%).

[3981] Melting point: 137-139° C.

[3982]¹H NMR (CDCl₃) δ1.28 (12H, s), 1.49 (3H, t, J=7.1 Hz), 2.17 (2H,s), 2.66-3.10 (2H, br), 4.23 (2H, q, J=7.1 Hz), 6.65 (1H, s), 7.33-7.41(2H, m), 7.94-7.97 (1H, m), 8.27 (1H, s).

Example 546

[3983]3-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenaminedihydrochloride

[3984]3-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine(9.36 g, 25.7 mmol) was dissolved in ethyl-acetate, 4 M hydrogenchloride/ethyl acetate solution was added thereto, and the mixture wasconcentrated under reduced pressure, crystallized from ethanol-ethylacetate to obtain the title compound (4.47 g, yield: 40%).

[3985] Melting point: 240° C. (decomposition).

[3986]¹H NMR (DMSO-d₆) δ1.26 (6H, s), 1.37 (3H, t, J=7.0 Hz), 1.42 (6H,s), 2.10-2.55 (2H, m), 3.00-3.30 (2H, m), 4.23 (2H, q, J=7.0 Hz),6.99-7.07 (3H, m), 7.19 (1H, d, J=7.6 Hz), 7.44 (1H, dd, J=8.2, 7.6 Hz).

Example 547

[3987][[4-[[[3-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]amino]carbonyl]phenyl]methyl]phosphonicacid diethyl ester hydrochloride

[3988] 1-Hydroxy-1H-benzotriazole monohydrate (327 mg, 2.13 mmol),triethylamine (0.95 mL, 6.79 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (483 mg,2.52 mmol) were added to a solution of3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenaminedihydrochloride (850 mg, 1.94 mmol) and4-[(diethoxyphosphinyl)methyl]benzoic acid (529 mg, 1.94 mmol) inN,N-dimethylformamide (6 mL) and the mixture was stirred at roomtemperature for 7 hours. 4-[(Diethoxyphosphinyl)methyl]benzoic acid (211mg, 0.776 mmol) was added to the mixture and the mixture was stirredunder the same condition for 12 hours. Ice water was poured into thereaction mixture, which was extracted three times with ethyl acetate.The combined organic layer was washed with brine, dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas subjected to a column chromatography on a basic silica gel(hexane/ethyl acetate 1:1 followed by ethyl acetate) to obtain a freebase of the title compound. This was dissolved in ethyl acetate,combined with 4 M hydrogen chloride/ethyl acetate solution, concentratedunder reduced pressure, crystallized from ethanol-duisopropyl ether toobtain the title compound (682 mg, yield: 54%).

[3989] Melting point: i90-191° C.

[3990]¹H NMR (DMSO-d₆-D₂O (1 drop)) δ1.18 (6H, t, J=7.1 Hz), 1.25 (6H,s), 1.38 (3H, t, J=7.0 Hz), 1.42 (6H, s), 2.20-2.32 (1H, m), 2.40-2.53(1H, m), 3.00-3.30 (2H, m), 3.35 (2H, d, J=21.9 Hz), 3.91-4.03 (4H, m),4.25 (2H, q, J=7.0 Hz), 7.09 (1H, s), 7.36 (1H, d, J=7.7 Hz), 7.44 (2H,dd, J=8.3, 2.3 Hz), 7.64 (1H, t, J=7.7 Hz), 7.94 (2H, d, J=8.3 Hz), 8.06(1H, d, J=7.7 Hz), 8.09 (1H, s), 10.59 (1H, s).

Example 548

[3991]6-(Ethylsulfinyl)-3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinoline

[3992] A solution of sodium metaperiodate (434 mg, 2.03 mmol) in water(2.5 mL) was added to a solution of6-(ethylthio)-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolinehydrochloride (326 mg, 0.811 mmol) in methanol (3.5 mL) and the mixturewas stirred at room temperature for 2 hours. Water was poured into thereaction mixture, which was combined with sodium hydrogen carbonate, andextracted twice with ethyl acetate. The combined organic layer waswashed with water and brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was subjected to acolumn chromatography on a basic silica gel (hexane/ethyl acetate 5:1),crystallized from diisopropyl ether-hexane to obtain the title compound(168 mg, yield: 54%).

[3993] Melting point: 146-147° C.

[3994]¹H NMR (CDCl₃) δ1.20-1.30 (15H, m), 2.19 (2H, s), 2.77 (2H, s),2.82-3.18 (2H, m), 7.41-7.42 (6H, m).

Example 549

[3995]3-[3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-6-(propylthio)furo[2,3-h]isoquinolin-1-yl]benzoicacid ethyl ester

[3996] 1.57 M n-butyllithium /hexane solution (42.3 mL, 66.4 mmol) wastreated dropwise successively with a solution ofN,N,N′,N′-tetramethylethylenediamine (10.0 mL, 66.4 mmol) intetrahydrofuran (15 mL), a solution of7-bromo-2,3-dihydro-2,2-dimethyl-5-(2-methy-1-prpenyl)benzofuran (4.68g, 16.6 mmol) in tetrahydrofuran (15 mL) and a solution of n-propyldisulfide (20 g, 133 mmol) in tetrahydrofuran (15 mL) at -78° C., andthe mixture was allowed to warm to room temperature while stirring for15 hours. The reaction mixture was poured into a saturated aqueoussolution of ammonium chloride, and extracted twice with ethyl acetate.The combined organic layer was washed with brine, dried over magnesiumsulfate, filtered and concentrated under reduced pressure. The residuewas subjected to a column chromatography on a silica gel (hexanefollowed by hexane/ethyl acetate 50:1) to obtain an about 15:2 mixtureof2,3-dihydro-2,2-dimethyl-5-(2-methyl-1-propenyl)-7-(propylthio)benzofuranand 2,3-dihydro-2,2-dimethyl-5-(2-methyl-1-propenyl)benzofuran (4.11 g).

[3997] A suspension of the resultant mixture (1.01 g) and ethyl3-cyanobenzoate (601 mg, 3.43 mmol) in acetic acid (2 mL)-toluene (4.5mL) was treated dropwise with conc. sulfuric acid (0.38 mL, 7.20 mmol)with cooling in ice, and stirred at 60° C. for 1 hour. Ethanol (2.1 mL34.9 mmol) was added dropwise to the mixture, and the mixture wasstirred at the same temperature for 30 minutes. Ice water was pouredinto the reaction mixture, which was neutralized with sodium hydrogencarbonate, and extracted twice with ethyl acetate. The combined organiclayer was washed with brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was subjected to acolumn chromatography on a basic silica gel (hexane/ethyl acetate 50:1followed by 10:1), and subjected again to a column chromatography on asilica gel (hexane/ethyl acetate 10:1 followed by 5:1), crystallizedfrom hexane to obtain the title compound (136 mg, yield: 9%). The motherliquor was crystallized from hexane to obtain the second crystal of thetitle compound (78 mg, yield: 5%).

[3998] Melting point: 83-84° C.

[3999]¹H NMR (CDCl₃) b 1.05 (3H, t, J=7.3 Hz), 1.25 (6H, s), 1.29 (6H,s), 1.39 (3H, t, J=7.2 Hz), 1.64-1.76 (2H, m), 2.16 (2H, s), 2.68 (2H,s), 2.95 (2H, t, J=7.2 Hz), 4.39 (2H, q, J=7.2 Hz), 6.92 (1H, s), 7.48(1H, dd, J=7.8, 7.2 Hz), 7.62 (1H, d, J=7.8 Hz), 8.07-8.10 (2H, m).

Example 550

[4000]3-[6-(Ethylthio)-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]benzoicacid isopropyl ester

[4001] To a suspension of7-(ethylthio)-2,3-dihydro-2,2-dimethyl-5-(2-methyl-1-propenyl)benzofuran(811 mg, 3.21 mmol) and isopropyl 3-cyanobenzoate (552 mg, 2.92 mmol) inacetic acid (3 mL)-toluene (6 mL) was treated dropwise with conc.sulfuric acid (0.33 mL, 6.13 mmol) with cooling in ice, and stirred at70° C. for 1.5 hours. Ice water was poured into the reaction mixture,which was neutralized with sodium hydrogen carbonate and extracted twicewith ethyl acetate. The combined organic layer was washed with a brine,dried over sodium sulfate, filtered and concentrated under reducedpressure. The residue was subjected to a column chromatography on asilica gel (hexane/ethyl acetate 10:1) and crystallized from pentane toobtain the title compound (86 mg, yleld: 7%).

[4002] Melting point:. 108-110° C.

[4003]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.92 (6H, s), 1.34 (3H, t, J=7.5Hz), 1.36 (6H, d, J=6.3 Hz), 2.17 (2H, s), 2.69 (2H, s), 3.00 (2H, q,J=7.5 Hz), 5.20-5.33 (1H, m), 6.94 (1H, s), 7.48 (1H, t, J=7.8 Hz), 7.61(1H, dd, J=7.8, 1.5 Hz), 8.04 (1H, t, J=1.5 Hz), 8.09 (1H, dd, J=7.8,1.5 Hz).

Example 551

[4004]3-[5-(Cyanomethyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]benzoicacid methyl ester hydrochloride

[4005] Paraformaldehyde (94%) (841 mg, 26.3 mmol), sodium bromide (2.98g, 29.0 mmol) and conc. sulfuric acid (2.11 mL, 39.6 mmol) were added toa solution of3-[3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]benzoicacid methyl ester (4.99 g, 12.7 mmol) in acetic acid (6.5 mL) and themixture was stirred at 100° C. fort 11 hours. Methanol was addeddropwise at 75° C., and the mixture was stirred at the same temperaturefor 3 hours. Water was poured into the reaction mixture, which waswashed with diisopropyl ether, neutralized with sodium hydrogencarbonate, and extracted twice with ethyl acetate. The combined organiclayer was washed with 1 M aqueous solution of sodium hydroxide and abrine, dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was subjected to a column chromatographyon a silica gel (hexane/ethyl acetate 5:1) to obtain3-[5-(bromomethyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]benzoicacid methyl ester (1.30 g, yield: 21%) as an amorphous material.

[4006]¹H NMR (CDCl₃) δ1.28 (6H, s), 1.29 (6H, s), 2.12 (2H, s), 2.72(2H, s), 3.92 (3H, s), 4.05 (3H, s), 4.64 (2H, s), 7.48 (1H, t, J=7.9Hz), 7.61 (1H, dd, J=7.9, 1.6 Hz), 8.06 (1H, d, J=1.6 Hz), 8.08 (1H, dd,J=7.9, 1.6 Hz).

[4007] A solution of potassium cyanide (174 mg, 2.67 mmol) in water (2.5mL) was added to a solution of the resultant bromo-derivative (1.30 g,2.67 mmol) in N,N-dlmethylformamide (8 mL) and the mixture was stirredat room temperature for 1 hour. Ice water was poured into the reactionmixture, which was extracted twice with ethyl acetate. The combinedorganic layer was washed with brine, dried over sodium sulfate, filteredand concentrated under reduced pressure. The residue was subjected to acolumn chromatography on a basic silica gel (hexane/ethyl acetate 10:1followed by 5:1) to obtain a free base of the title compound. This wasdissolved in ethyl acetate, combined with 4 M hydrogen chloride/ethylacetate solution, concentrated under reduced pressure, crystallized fromethyl acetate to obtain the title compound (926 mg, yield: 74%).

[4008] Melting point: 186-188° C.

[4009]¹H NMR (DMS₆) δ1.25 (6H, s), 1.45 (6H, s), 2.15 (2H, s), 3.19 (2H,s), 3.91 (3H, s), 4.02 (2H, s), 4.07 (3H, s), 7.78 (1H, t, J=7.6 Hz),7.89 (1H, d, J=7.6 Hz), 8.21 (1H, s), 8.28 (1H, d, J=7.6 Hz).

Example 552

[4010]3-[5-(Cyanomethyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]benzoicacid hydrochloride

[4011] The title compound was obtained from3-[5-(cyanomethyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]benzoicacid methyl ester hydrochloride by the method similar to that in EXAMPLE80. Quantitative.

[4012] Melting point: 182-184° C. (acetone-ethyl acetate).

[4013]¹H NMR (DMSO-d₆) δ1.25 (6H, s), 1.45 (6H, s), 2.16 (2H, s), 3.19(2H, s), 4.02 (2H, s), 4.07 (3H, s), 7.75 (1H, t, J=7.8 Hz), 7.87 (1H,d, J=7.8 Hz), 8.18 (1H, s), 8.26 (1H, d, J=7.8 Hz).

Example 553

[4014]3-[5-(Cyanomethyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]-N-methylbenzamidehydrochloride

[4015] N,N′-Carbonyldiimidazole (118 mg, 0.728 mmol) was added to asolution of3-[5-(cyanomethyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]benzoicacid hydrochloride (331 mg, 0.728 mmol) in N,N-dimethylformamide (3 mL)and the mixture was stirred at room temperature for 40 minutes.Triethylamine (0.11 mL, 0.801 mmol) and methylamine hydrochloride (54mg, 0.801 mmol) were added to the mixture, and the mixture was stirredat room temperature for 4 hours. Ice water was poured into the reactionmixture, which was extradted twice with ethyl acetate. The combinedorganic layer was washed with 1 M aqueous solution of sodium hydroxide,water and brine, dried over sodium sulfate, filtered and concentratedunder reduced pressure. The residue was subjected to a columnchromatography on a basic silica gel (hexane/ethyl acetate 1:1) toobtain a free base of the title compound. This was dissolved in ethylacetate, combined with 4 M hydrogen chloride/ethyl acetate solution,concentrated under reduced pressure, crystallized from ethyl acetate toobtain the title compound (139 mg, yield: 41%).

[4016] Melting point: 160-162° C.

[4017]¹H NMR (DMSO-d₆) δ1.26 (6H, s), 1.45 (6H, s), 2.18 (2H, s), 2.81(3H, d, J=4.0 Hz), 3.18 (2H, s), 4.02 (2H, s), 4.07 (3H, s), 7.67-7.74(2H, m), 8.12-8.19 (2H, m), 8.77 (1H, br s).

Example 554

[4018]3-[5-(Cyanomethyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]-N-(hexahydro-2-oxo-1H-azepin-3-yl)benzamide

[4019] Triethylamine (0.10 mL, 0.743 mmol) and N,N′-carbonyldiimidazole(120 mg, 0.743 mmol) were added to a solution of3-[5-(cyanomethyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]benzoicacid hydrochloride (338 mg, 0.743 mmol) in N,N-dimethylformamide (3 mL)and the mixture was stirred at room temperature for 40 minutes.3-Aminohexahydro-2H-azepin-2-one (101 mg, 0.784 mmol) was added to themixture and the mixture was stirred at room temperature for 4.5 hours.Ice water was poured into the reaction mixture, which was extractedtwice with ethyl acetate. The combined organic layer was washed with 1 Maqueous solution of sodium hydroxide, water and a brine, dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresidue was subjected to a column chromatography on a basic silica gel(hexane/ethyl acetate 1:2), crystallized from ethyl acetate to obtainthe title compound (206 mg yield: 52% )

[4020] Melting point: 130-132° C.

[4021]¹H NMR (CDCl₃) δ1.28 (12H, s), 1.48-1.70 (2H, m), 1.80-2.30 (4H,m), 2.13 (2H, s), 2.69 (2H, s), 3.25-3.40 (2H, m), 3.74 (2H, s), 4.04(3H, s), 4.69-4.77 (1H, m), 6.15 (1H, br s), 7.47-7.49 (2H, m), 7.71(1H, d, J=5.6 Hz), 7.88-7.95 (2H, m).

Example 555

[4022]N-[3-[5-(Cyanomethyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]benzoyl]-2-methylalanineethyl ester

[4023] 1-Hydroxy-1H-benzotriazole monohydrate (829 mg, 5.41 mmol),triethylamine (2.40 mL, 17.2 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimlde hydrochloride (1.23 g,6.40 mmol) were added to a solution of3-[5-(cyanomethyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]benzoicacid hydrochloride (2.24 g, 4.92 mmol) and ethyl 2-aminoisobutyratehydrochloride (907 mg, 5.41 mmol) in N,N-dimethylformamide (10 mL) andthe mixture was stirred at room temperature for 1.5 hours. Ice water waspoured into the reaction mixture, which was extracted three times withethyl acetate. The combined organic layer was washed with 0.5 M aqueoussolution of sodium hydroxide and a brine, dried over sodium sulfate,filtered and concentrated under reduced pressure. The residue wassubjected to a column chromatography on a basic silica gel (hexane/ethylacetate 3:1 followed by 2:1), crystallized from ethyl acetate-diethylether to obtain the title compound (1.50 g, yield: 57%).

[4024] Melting point: 126-128° C.

[4025]¹H NMR (CDCl₃) δ1.29 (3H, t, J=7.0 Hz), 1.29 (12H, s), 1.68 (6H,s), 2.13 (2H, s), 2.69 (2H, s), 3.75 (2H, s), 4.04 (3H, s), 4.24 (2H, q,J=7.0 Hz), 6.89 (1H, s), 7.46-7.48 (2H, m), 7.81-7.89 (2H, m).

Example 556

[4026]N-[3-[5-(Cyanomethyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]benzoyl]-2-methylalaninehydrochloride

[4027] 5 M aqueous solution of sodium hydroxide (2 mL) was added to asolution ofN-[3-[5-(cyanomethyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]benzoyl]-2-methylalanineethyl ester (1.05 g, 1.98 mmol) in ethanol (8 mL) and the mixture wasstirred at room temperature for 1 hour. The reaction mixture was madeacidic with 5 M hydrochloric acid, and the solvent was distilled off.The residue was dissolved in methanol, and the insolubles were filteredoff. The filtrate was concentrated under reduced pressure, and thisprocedure was repeated three times. The residue was crystallized fromacetone-ethyl acetate to obtain the title compound (1.04 g, yield: 97%).

[4028] Melting point: 191-194° C.

[4029]¹H NMR (DMSO-d₆) δ1.27 (6H, br s), 1.42 (6H, br s), 1.48 (6H, s),2.24 (2H, s), 3.05-3.30 (2H, m), 3.95-4.13 (5H, m), 7.65-7.80 (2H, m),8.18-8.30 (2H, m), 8.80 (1H, s).

Example 557

[4030]N-(2-Amino-2-oxoethyl)-3-[5-(cyanomethyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]benzamidehydrochloride

[4031] 1-Hydroxy-1H-benzotriazole monohydrate (377 mg, 2.46 mmol),triethylamine (1.09 mL, 7.84 mmol) and1-ethyl-3-(3-dimethylamlnopropyl)carbodiimide hydrochloride (559 mg,2.91 mmol) were added to a solution of3-[5-(cyanomethyl)-3,4,8.9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]benzoicacid hydrochloride (1.02 g, 2.24 mmol) and glycinamide hydrochloride(248 mg, 2.24 mmol) in N,N-dimethylformamide (6 mL) and the mixture wasstirred at room temperature for 6 hours. Water was poured into thereaction mixture, which was extracted three times with ethyl acetate.

[4032] The combined organic layer was washed with brine, dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresidue was subjected to a column chromatography on a basic silica gel(ethyl acetate/methanol 100:1) to obtain a free base of the titlecompound. This was dissolved in ethyl acetate, combined with 4 Mhydrogen chloride/ethyl acetate solution, concentrated under reducedpressure, triturated with diethyl ether to obtain the title compound(425 mg, yield: 37%).

[4033] Amorphous.

[4034]¹H NMR (DMSO-d₆) δ1.27 (6H, s), 1.46 (6H, s), 2.22 (2H, s), 3.20(2H, s), 3.85 (2H, d, J=3.8 Hz), 4.03 (2H, s), 4.08 (3H, s), 7.09 (1H,s), 7.47 (1H, s), 7.74-7.80 (2H, m), 8.18-8.25 (2H, m), 8.99 (1H, s).

Example 558

[4035]N-(2-Amino-1,1-dimethyl-2-oxoethyl)-3-[5-(cyanomethyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]benzamide

[4036] 1-Hydroxy-1H-benzotrlazole ammonium salt (176 mg, 1.16 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (240 mg,1.25 mmol) were added to a solution ofN-[3-[5-(cyanomethyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]benzoyl]-2-methylalaninehydrochloride (521 mg, 0.965 mmol) in N,N-dimethylformamide (5 mL) andthe mixture was stirred at room temperature for 10 minutes.Triethylamine (0.40 mL, 2.90 mmol) was added to the mixture and themixture was stirred at room temperature for 3 hours. Ice water waspoured into the reaction mixture, which was extracted twice with ethylacetate. The combined organic layer was washed with water and brine,dried over sodium sulfate, filtered and concentrated under reducedpressure. The residue was subjected to a column chromatography on abasic silica gel (hexane/ethyl acetate 1:2 followed by ethyl acetate),crystallized from ethyl acetate-diisopropyl ether to obtain the titlecompound (323 mg, yield: 67%).

[4037] Melting point: 217-219° C.

[4038]¹H NMR (CDCl₃) δ1.29 (12H, s), 1.71 (6H, s), 2.14 (2H, s), 2.69(2H, s), 3.74 (2H, s), 4.04 (3H, s), 5.44 (1H, br s), 6.42 (1H, br s),7.26-7.27 (1H, m), 7.47-7.48 (2H, m), 7.84-7.89 (2H, m).

Example 559

[4039]3-[5-(Cyanomethyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]-N-[1,1-dimethyl-2-oxo-2-[(2-oxo-3-pyrrolidinyl)amino]ethyl]benzamlde

[4040] 1-Hydroxy-1H-benzotriazole monohydrate (138 mg, 0.904 mmol),triethylamine (0.29 mL, 2.06 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (205 mg,1.07 mmol) were added to a solution ofN-[3-[5-(cyanomethyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]benzoyl]-2-methylalaninehydrochloride (444 mg, 0.822 mmol) and D,L-3-amino-2-pyrrolidinone (82mg, 0.822 mmol) in N,N-dimethylformamide (4 mL) and the mixture wasstirred at room temperature for 6 hours. Ice water was poured into thereaction mixture, which was extracted three times with ethyl acetate.The combined organic layer was washed with brine, dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas subjected to a column chromatography on a basic silica gel (ethylacetate/methanol 100:1 followed by 10:1), and the resultant crystalswere washed with diisopropyl ether to obtain the title compound (157 mg,yield: 33%).

[4041] Melting point: 137-139° C.

[4042]¹H NMR (CDCl₃) δ1.29 (12H, s), 1.70 (3H, s), 1.72 (3H, s),1.94-2.08 (1H, m), 2.14 (2H, s), 2.69 (2H, s), 2.70-2.85 (1H, m),3.16-3.45 (2H, m), 3.75 (2H, s), 4.04 (3H, s), 4.26-4.34 (1H, m), 5.99(1H, s), 6.91 (1H, d, J=3.6 Hz), 7.13 (1H, s), 7.44-7.49 (2H, m), 7.87(2H, s).

Example 560

[4043]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenyl-5-furo[2,3-h]-isoquinolinecarboxaldehydehydrochloride

[4044] Manganese dioxide (4.90 g, 56.4 mmol) was added to a solution of3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-5-furo[2,3-h]isoquinolinemethanol(1.03 g, 2.82 mmol) in chloroform (15 mL) and the mixture was stirred atroom temperature for 2 hours, and at 50° C. for 15 hours. Inorganicsalts were filtered off and the filtrate was concentrated under reducedpressure. The residue was subjected to a column chromatography on asilica gel (hexane/ethyl acetate 5:1) to obtain a free base of the titlecompound. This was dissolved in ethyl acetate, combined with 4 Mhydrogen chloride/ethyl acetate solution, concentrated under reducedpressure, crystallized from ethyl acetate-hexane to obtain the titlecompound (344 mg, yield: 31%).

[4045] Melting point: 136-139° C.

[4046]¹H NMR (DMSO-d₆) δ1.29 (6H, s), 1.43 (6H, s), 2.24 (2H, s), 3.40(2H, s), 4.14 (3H, s), 7.60-7.82 (5H, m), 10.42 (1H, s).

Example 561

[4047]3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenyl-5-furo[2,3-h]isoquinolinecarbonitrile

[4048] Hydroxylamine hydrochloride (30 mg, 0.4.35 mmol) was added to asolution of3,4,8,9-tetrahydro-6-methoxy-3,3,8,8,-tetramethyl-1-phenyl-5-furo[2,3-h]isoquinolinecarboxaldehydehydrochloride (116 mg, 0.290 mmol) in formic acid (1 mL) and the mixturewas stirred at 100° C. for 3 hours. Water was poured into the reactionmixture, which was neutralized with conc. aqueous ammonia and extractedtwice with ethyl acetate. The combined organic layer was washed withwater and brine, dried over sodium sulfate, filtered and concentratedunder reduced pressure. The residue was subjected to a columnchromatography on a silica gel (hexane/ethyl acetate 5:1), and theresultant crystals were washed with diisopropyl ether-hexane to obtainthe title compound (55 mg, yield: 53%).

[4049] Melting point: 166-168° C.

[4050]¹H NMR (CDCl₃) δ1.27 (6H, s), 1.30 (6H, s), 2.19 (2H, s), 2.87(2H, s), 4.13 (3H, s), 7.35-7.43 (5H, m).

Example 562

[4051]3-[5-(Cyanomethyl)-6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]benzoicacid ethyl ester hydrochloride

[4052] Paraformaldehyde (94%) (613 mg, 19.2 mmol), sodium bromide (2.17g, 21.1 mmol) and conc. sulfuric acid (1.71 mL, 32.0 mmol) were added toa solution of3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid (5.03 g, 12.8 mmol) in acetic acid (10 mL) and the mixture wasstirred at 105° C. for 14 hours. Paraformaldehyde (94%) (409 mg, 12.8mmol), sodium bromide (1.45 g, 14.1 mmol) and conc. sulfuric acid (0.68mL, 12.8 mmol) were further added to the mixture and the mixture wasstirred at 115° C. for 10 hours. The reaction mixture was adjusted at pH8 with 5 M aqueous solution of sodium hydroxide, and extracted withethyl acetate. The organic layer was washed with brine, dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresidue was dissolved in ethanol (12 mL) and thionyl chloride (0.65 mL,8.94 mmol) was added thereto with cooling in ice, and the mixture wasstirred at room temperature for 24 hours. The solvent was distilled offunder reduced pressure, and the residue was combined with water,neutralized with sodium hydrogen carbonate, and extracted twice withethyl acetate. The combined organic layer was washed with brine, driedover sodium sulfate, filtered and concentrated under reduced pressure.The residue was subjected to a column chromatography on a silica gel(hexane/ethyl acetate 5:1) to obtain3-[5-(bromomethyl)-6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]benzoicacid ethyl ester (170 mg, yield: 3%) as an oil.

[4053]¹H NMR (CDCl₃) δ1.27 (6H, s), 1.28 (6H, s), 1.37-1.42 (6H, m),2.12 (2H, s), 2.77 (2H, s), 4.31 (2H, q, J=7.1 Hz), 4.39 (2H, q, J=7.1Hz), 4.76 (2H, s), 7.48 (1H, t, J=7.8 Hz), 7.61 (1H, dd, J=7.8, 1.5 Hz),8.05-8.07 (1H, m), 8.09 (1H, dt, J=7.8, 1.5 Hz).

[4054] A solution of sodium cyanide (18 mg, 0.362 mmol) in water (0.5mL) was added to absolution of the resultant bromo-derivative (170 mg,0.330 mmol) in N,N-dimethylformamide (0.7 mL) and the mixture wasstirred at room temperature for 1 hour and at 60° C. for 2 hours. Waterwas poured into the reaction mixture, which was extracted twice withethyl acetate. The combined organic layer was washed with brine, driedover sodium sulfate, filtered and concentrated under reduced pressure.The residue was subjected to a column chromatography on a silica gel(hexane/ethyl acetate 3:1) to obtain a free base of the title compound.This was dissolved in ethyl acetate, combined with 4 M hydrogenchloride/ethyl acetate solution, concentrated under reduced pressure,crystallized from ethyl acetate to obtain the title compound (111 mg,yield: 68%).

[4055] Melting point: 126-128° C.

[4056]¹H NMR (DMSO-d₄) δ1.25 (6H, s), 1.30-1.37 (6H, m), 1.44 (6H, s),2.16 (2H, s), 3.16 (2H, s), 4.01 (2H, s), 4.33-4.47 (4H, m), 7.73-7.90(2H, m), 8.18-8.29 (2H, m).

Example 563

[4057] (S)-N-(2-Oxo-3-azetidinyl)-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide

[4058]3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid hydrochloride (0.25 g, 0.6 mmol) was dissolved inN,N-dimethylformamide (3 mL), N-ethyldiisopropylamine (0.104 mL, 0.6mmol) was added thereto, and the mixture was stirred for 5 minutesN,N′-Carbonyldiimidazole (0.107 g, 0.66 mmol) was added to the mixtureand the mixture was stirred at room temperature for 30 minutes.(S)-3-Amino-2-azetidinone (0.057 g, 0.66 mmol) was added to the reactionmixture and the mixture was stirred at room temperature for 15 hours.Ice water was added to the reaction mixture, which was extracted twicewith ethyl acetate. The extract was washed with an aqueous solution ofsodium chloride, dried over sodium sulfate, filtered, and concentratedunder reduced pressure The residue was subjected to a columnchromatography on a silica gel, eluted with ethylacetate/methanol/triethylamine (95:5:1) to collect the intendedfraction, which was concentrated to obtain the title compound (0.171 g,yield: 63%). The title compound was recrystallized from diethyl ether.

[4059] Melting point: 154-157° C.

[4060]¹H NMR (CDCl₃) δ1.29 (6H, s), 1.31 (6H, s), 2.16 (2H, s), 2.61(2H, s), 3.22 (1H, br), 3.60 (1H, t, J=5 Hz), 3.93 (3H, s), 5.10 (1H,br), 6.32 (1H, br), 6.61 (1H, s), 7.4-8.0 (4H, m), 8.03 (1H, br).

Example 564

[4061]N-(2-Oxo-3-pyrrolidinyl)-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide

[4062]3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid hydrochloride (0.25 g, 0.6 mmol) was dissolved inN,N-dimethylformamide (3 mL), N-ethyldiisopropylamine (0.104 mL, 0.6mmol) followed by N,N′-carbonyldiimidazole (0.107 g, 0.66 mmol) wereadded thereto, and the mixture was stirred at room temperature for 1hour. 3-Amino-2-pyrrolidinone (0.067 g, 0.66 mmol) was added to thereaction mixture and the mixture was stirred at room temperature for 15hours. Ice water was added to the reaction mixture, which was extractedtwice with ethyl acetate. The extract was washed with an aqueoussolution of sodium chloride, dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was subjected to acolumn chromatography on a silica gel, eluted with ethylacetate/methanol (10:1) to collect the intended fraction, which wasconcentrated to obtain the title compound (0.184 g, yield: 66%). Thetitle compound was recrystallized from diethyl ether.

[4063] Melting point: 191-193° C.

[4064]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.30 (6H, s), 1.7-2.3 (2H, m), 2.15(2H, s), 2.70 (2H, s), 3.2-3.5 (2H, m), 3.93 (3H, s), 4.62 (1H, br),6.62 (1H, s), 7.00 (1H, br), 7.4-8.0 (4H, m), 7.70 (1H, br).

Example 565

[4065]3,4,8,9-Tetrahydro-6-methoxy-4,4,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinoline

[4066]N-[2-(2,3-Dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-2-methylpropyl]benzamide(0.269 g, 0.76 mmol) was suspended in phosphorus oxychloride (3.5 g,22.8 mol) and the mixture was stirred at 100-105° C. for 2 hours. Aftercooling to room temperature, the reaction mixture was poured into anaqueous solution of sodium carbonate while cooling in ice with stirring,adjusted at pH 7 and extracted twice with ethyl acetate. The extract waswashed with an aqueous solution of sodium chloride, dried over magnesiumsulfate, filtered and concentrated under reduced pressure. The residuewas subjected to a column chromatography on a silica gel, eluted withhexane/ethyl acetate/triethylamine (67:33:1) to collect the intendedfraction, which was concentrated to obtain the title compound (0.175 g,yield: 68%). The title compound was recrystallized from diethylether/hexane (1:2).

[4067] Melting point: 137-139° C.

[4068]¹H NMR (CDCl₃) δ1.28 (6H, s), 1.32 (6H, s), 2.26 (2H, s), 3.63(2H, s), 3.95 (3H, s), 6.79 (1H, s), 7.42 (5H, s).

Example 566

[4069]3-(3,4,8,9-tetrahydro-6-methoxy-4,4,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzonitrile

[4070]3-Cyano-N-[2-(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-2-methylpropyl]benzamide(0.955 g, 2.52 mmol) was suspended in phosphorus oxychloride (11.6 g,75.6 mmol) and the mixture was stirred at 100-105° C. for 2 hours. Aftercooling to room temperature, the reaction mixture was poured into anaqueous solution of potassium carbonate while cooling in ice withstirring, and adjusted at pH 7 and extracted twice with ethyl acetate.The extract was washed with an aqueous solution of sodium chloride,dried over magnesium sulfate, filtered and concentrated under reducedpressure. The residue was subjected to a column chromatography on asilica gel, eluted with hexane/ethyl acetate (3:2) to collect theintended fraction, which was concentrated to obtain the title compound(0.65 g, yield: 71%). The title compound was recrystallized from diethylether.

[4071] Melting point: 178-180° C.

[4072]¹H NMR (CDCl₃) δ1.24 (6H, s), 1.27 (6H, s), 2.23 (2H, s), 3.64(2H, s), 3.96 (3H, s), 6.81 (1H, s), 7.4-7.9 (4H, m).

Example 567

[4073]3-(3,4,8,9-Tetrahydro-6-methoxy-4,4,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide

[4074]3-(3,4,8,9-Tetrahydro-6-methoxy-4,4,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzonitrile(0.446 g, 1.23 mmol) was dissolved in methanol (7 mL), 1 M aqueoussolution of sodium hydroxide (1.97 mL) and 30% aqueous solution ofhydrogen peroxide (0.28 mL) were added thereto with cooling in ice, andthe mixture was stirred at room temperature for 20 hours. Methanol wasdistilled off under reduced pressure, and the residue was diluted withwater and extracted twice with ethyl acetate. The extract was washedwith an aqueous solution of sodium chloride, dried over magnesiumsulfate, filtered and concentrated under reduced pressure. The residuewas recrystallized from ethyl acetate to obtain the title compound(0.275 g, yield: 59%).

[4075] Melting point: 191-193° C.

[4076]¹H NMR (CDCl₃) δ1.28 (6H, s), 1.31 (6H, s), 2.24 (2H, s), 3.63(2H, s), 3.95 (3H, s), 5.85 (1H, br), 6.35 (1H, br), 6.81 (1H, s),7.4-7.9 (4H, m).

Example 568

[4077]3,4,8,9-Tetrahydro-6-methoxy-4,4,8,8-tetramethyl-1-furo[2,3-h]isoquinolinecarboxylicacid ethyl ester

[4078] Ethyl[[2-(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-2-methylpropyllamino]oxoacetate(0.510 g, 0.76 mmol) was dissolved in phosphorus oxychloride (6.72 g,43.8 mmol) and stirred at 100-105° C. for 3 hours. After cooling to roomtemperature, the reaction mixture was poured into 2 M aqueous solutionof sodium hydroxide (30 mL) while cooling in ice with stirring, adjustedat pH 5 with sodium hydrogen carbonate, and extracted twice with ethylacetate. The extract was washed with an aqueous solution of sodiumchloride, dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was subjected to a column chromatographyon a silica gel, eluted with hexane/ethyl acetate (2:1) to collect theintended fraction, which was concentrated to obtain the title compound(0.286 g, yield: 68%). The title compound was recrystallized fromdlethyl ether/hexane (1:1).

[4079] Melting point: 117-121° C.

[4080]¹H NMR (CDCl₃) δ1.23 (6H, s), 1.26 (3H, t, J=7 Hz), 1.49 (6H, s),2.99 (2H, s), 3.61 (2H, s), 3.94(3H, s), 4.12 (2H, q, J=7 Hz), 6.75 (1H,s).

Example 569

[4081]1-(3-Bromophenyl)-3,4,8,9-tetrahydro-6-methoxy-4,4,8,8-tetramethylfuro[2,3-h]isoquinoline

[4082] Phosphorus oxychlorjde (3.3 mL, 35 mmol) was added to asuspension of3-bromo-N-[2-(2,3-dihydro-7-methoxy-2,2-dimethyl-5-benzofuranyl)-2-methylpropyl]benzamide(1.28 g, 2.96 mmol) in toluene (25 mL) and the mixture was heated underreflux for 3.5 hours. The reaction mixture was poured into ice water,and neutralized with 5 M aqueous solution of sodium hydroxide withcooling in ice. The organic layer was separated, and the aqueous layerwas extracted with toluene. The combined organic layer was washed twicewith water, and concentrated under reduced pressure. The residue wassubjected to a column chromatography on a silica gel (hexane/ethylacetate 4:1 followed by 2:1) and recrystallized from hexane to obtainthe title compound (741 mg, yield: 60%).

[4083] Melting point: 127-129° C.

[4084]¹H NMR (CDCl₃) δ1.26 (6H, s), 1.35 (6H, s) 2.31 (2H, s), 3.63 (2H,s), 3.95 (3H, s), 6.79 (1H, s), 7.28 (1H, t, J=7.7 Hz), 7.38 (1H, dt,J=7.7, 1.6 Hz), 7.55 (1H, dt, J=7.7, 1.6 Hz), 7.61 (1H, t, H=1.6 Hz).

Example 570

[4085]3′-(3,4,8,9-Tetrahydro-6-methoxy-4,4,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-amine

[4086] A suspension of1-(3-bromophenyl)-3,4,8,9-tetrahydro-6-methoxy-4,4,8,8-tetramethylfuro[2,3-h]isoquinoline(607 mg, 1.46 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (353 mg, 1.61mmol), sodium carbonate (388 mg, 3.66 mmol) andtetrakis(triphenylphosphine)palladium (0) (34 mg, 0.029 mmol) in1,2-dimethoxyethane (4.5 mL), ethanol (2 ml) and water (1.5 mL) wasstirred at 80° C. for 14-hours under nitrogen atmosphere. The reactionmixture was combined with water, and extracted twice with ethyl acetate.The combined organic layer was washed with water and brine, driedthrough sodium sulfate-basic silica gel (eluting with ethyl acetate),and concentrated under reduced pressure. The residue was subjected to acolumn chromatography on a basic silica gel(hexane/ethyl acetate 10:1followed by 1:1), recrystallized from methanol-diethyl ether to obtainthe title compound (400 mg, yield: 64%).

[4087] Melting point: 232-234° C.

[4088]¹H NMR (CDCl₃) δ1.29 (6H, s), 1.30 (6H, s), 2.34 (2H, s), 3.64(2H, s), 3.73 (2H, br s), 3.96 (3H, s), 6.74 (2H, d, J=8.4 Hz), 6.81(1H, s), 7.32 (1H, dt, J=7.7, 1.5 Hz), 7.37-7.49 (3H, m), 7.56-7.63 (2H,m).

Example 571

[4089]N-[3′-(3,4,8,9-Tetrahydro-6-methoxy-4,4,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-yl]acetamide

[4090] By the method similar to that in Example 30,3′-(3,4,8,9-tetrahydro-6-methoxy-4,4,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-aminewas employed to obtain the title compound. yield: 57%.

[4091] Melting point: 223-227° C. (ethyl acetate-diethyl ether).

[4092]¹H NMR. (CDCl₃) δ1.29 (6H, s), 1.31 (6H, s), 2.15-2.21 (3H, m),2.33 (2H, s), 3.65 (2H, s), 3.96 (3H, s), 6.81 (1H, s), 7.26-7.65 (9H,m).

Example 572

[4093]1-(3-Bromophenyl)-3,4,8,9-tetrahydro-4,4,8,8-tetramethyl-6-furo[2,3-h]isoquinolinol

[4094] 48% Hydrobromic acid (50 mL) was added to1-(3-Bromophenyl)-3,4,8,9-tetrahydro-6-methoxy-4,4,8,8-tetramethylfuro[2,3-h]isoquinoline(4.73 g, 11.4 mmol) and the mixture was heated under reflux for 22hours. The reaction mixture was cooled with ice, neutralized with conc.aqueous ammonia, and extracted twice with ethyl acetate. The combinedorganic layer was washed twice with water, and concentrated underreduced pressure. The residue was crystallized from ethylacetate-diethyl ether to obtain the title compound (3.96 g, yield: 87%).

[4095] Melting point: 230-235° C.

[4096]¹H NMR (CDCl₃) δ1.21 (6H, s), 1.32 (6H, s), 2.29 (2H, s), 3.59(2H, s), 6.74 (1H, s), 7.27 (1H, t, J=7.8 Hz), 7.40 (1H, dt, J=7.8, 1.6Hz), 7.55 (1H, dt, J=7.8, 1.6 Hz), 7.60 (1H, t, J=1.6 Hz).

Example 573

[4097][3′-(3,4,8,9-Tetrahydro-6-hydroxy-4,4,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-yl]carbamicacid phenylmethyl ester

[4098] A suspension of1-(3-bromophenyl)-3,4,8,9-tetrahydro-4,4,8,8-tetramethyl-6-furo[2,3-h]isoquinolinol(2.40 g, 6.00 mmol),[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyllcarbamic acidphenylmethyl ester (2.54 g, 7.19 mmol), sodium carbonate (1.59 g, 15.0mmol) and tetrakis(triphenylphosphine)palladium(0) (139 mg, 0.120 mmol)in 1,2-dimethoxyethane (20 mL), ethanol (10 mL) and water (10 mL) wasstirred at 85° C. for 16 hours under nitrogen atmosphere. The reactionmixture was combined with ethyl acetate and water, and the organic layerwas separated, and the aqueous layer was extracted with ethyl acetate.The combined organic layer was washed with brine, dried through sodiumsulfate-silica gel (eluting with ethyl acetate), and concentrated underreduced pressure. The residue was subjected to a column chromatographyon a basic silica gel (hexane/ethyl acetate 1:2 followed by ethylacetate), crystallized from ethyl acetate-chloroform to obtain the titlecompound (2.63 g, yield: 80%).

[4099] Melting point: 161-165° C.

[4100]¹H NMR (DMSO-d₆) δ1.15 (6H, s), 1.19 (6H, s), 2.25 (2H, s), 3.48(2H, s), 5.17 (2H, s), 6.74 (1H, s), 7.31-7.75 (13H, m), 9.74 (1H, s),9.91 (1H, s).

Example 574

[4101][3′-[3,4,8,9-Tetrahydro-4,4,8,8-tetramethyl-6-[[(trifluoromethyl)sulfonylloxy]furo[2,3-h]isoquinolin-1-yl][1,1′-biphenyl]-4-yl]carbamicacid phenylmethyl ester

[4102] The title compound was obtained from[3′-(3,4,8,9-tetrahydro-6-hydroxy-4,4,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-yl]carbamicacid phenylmethyl ester by the method similar to that in EXAMPLE 95.Yield: 92%.

[4103] Amorphous.

[4104]¹H NMR (CDCl₃) δ1.28 (6H, s), 1.30 (6H, s), 2.37.(2H, s), 3.70(2H, s), 5.22 (2H, s), 6.80 (1H, br s), 7.08 (1H, s), 7.31-7.51 (9H, m),7.57 (2H, d, J=8.7 Hz), 7.62-7.68 (2H, m).

Example 575

[4105][3′-(3,4,8,9-Tetrahydro-4,4,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-yl]carbamicacid phenylmethyl ester

[4106] Formic acid (0.30 mL, 8.0 mmol) was added to a solution of[3′-[3,4,8,9-tetrahydro-4,4,8,8-tetramethyl-6-[[(trifluoromethyl)sulfonyl]oxy]furo[2,3-h]isoguinolin-1-yl][1,1′-biphenyl]-4-yl]carbamicacid phenylmethyl ester (2.74 g, 4.04 mmol), triethylamine (1.7 mL, 12mmol), palladium acetate (II) (23 mg, 0.10 mmol) and triphenylphosphine(53 mg, 0.20 mmol) in N,N-dimethylformamide (8 mL) and the mixture wasstirred at 70° C. for 4 hours under nitrogen atmosphere. The reactionmixture was combined with water and a saturated aqueous solution ofsodium hydrogen carbonate, and extracted twice with ethyl acetate. Thecombined organic layer was washed twice with water, and concentratedunder reduced pressure. The residue was subjected to a columnchromatography on a basic silica gel (hexane/ethyl acetate 2:1),crystallized from ethyl acetate-diethyl ether to obtain the titlecompound (1.72 g, yield: 80%).

[4107] Melting point: 126-129° C.

[4108]¹H NMR (CDCl₃) δ1.27 (6H, s), 1.28 (6H, s), 2.32 (2H, s), 3.68(2H, s), 5.22 (2H, s), 6.77 (1H, br s), 6.83 (1H, d, J=8.4 Hz), 7.19(1H, d, J=8.4 Hz), 7.31-7.50 (9H, m), 7.55-7.68 (4H,

Example 576

[4109]3′-(3,4,8,9-Tetrahydro-4,4,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-aminedihydrobromide

[4110] 25% Hydrobromic acid/acetic acid solution (7 mL) was added to asolution of[3′-(3,4,8,9-tetrahydro-4,4,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)1,1′-biphenyl]-4-yl]carbamic acid phenylmethyl ester (1.90 g, 3.58 mmol)in chloroform (20 mL) and the mixture was stirred at room temperaturefor 3 hours. The reaction mixture was concentrated under reducedpressure, and the residue was combined with diethyl ether, and the solidwas recovered by filtration to obtain the title compound (1.97 g, 99%).

[4111] Melting point: 206-210° C.

[4112]¹H NMR (DMSO-d₆) δ1.21 (3H, s), 1.25 (3H, s), 1.37 (6H, s),2.25-2.50 (2H. m), 3.70-3.90 (2H, m), 7.15-7.32 (2H, m), 7.27 (1H, d,J=8.4 Hz), 7.50 (1H, d, J=8.4 Hz), 7.62-7.70 (1H, m), 7.72-7.85 (3H, m),8.05-8.07 (1H, m), 8.08 (1H, d, J=7.8 Hz).

Example 577

[4113]N-[3′-(3,4,8,9-Tetrahydro-4,4,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-yl]acetamide

[4114] A solution of sodium carbonate (t185 mg, 1.75 mmol) in water (1mnL) was added to a suspension of3′-(3,4,8,9-tetrahydro-4,4,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-aminedihydrobromide (279 mg, 0.500 mmol) in tetrahydrofuran (1 mL). Theresultant mixture was cooled with ice, treated dropwise with acetylchloride (46 μL, 0.65 mmol), and stirred at the same temperature for 15minutes. The reaction mixture was combined with water, and extractedtwice with chloroform. The combined organic layer was washed with brine,dried over sodium sulfate, filtered and concentrated under reducedpressure. The residue was crystallized from ethyl acetate-diethyl etherto obtain the title compound (149 mg, 68%).

[4115] Melting point: 246-249° C.

[4116]¹H NMR (CDCl₃) δ1.27 (6H, s), 1.29 (6H, s), 2.19 (3H, s), 2.32(2H, s), 3.68 (2H, s), 6.83 (1H, d, J=8.1 Hz), 7.19 (1H, d, J=8.1 Hz),7.36-7.43 (2H, m), 7.47 (1H, t, J=7.5 Hz), 7.57 (4H, s), 7.61-7.68 (2H,m).

Example 578

[4117]N-[3′-(3,4,8,9-Tetrahydro-4,4,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-yl]propanamide

[4118] The title compound was obtained from propionyl chloride by themethod similar to that in EXAMPLE 577. Yield: 56%.

[4119] Melting point: 215-218° C. (ethyl acetate-diethyl ether).

[4120]¹H NMR (CDCl₃) δ1.23-1.31 (3H, m), 1.27 (6H, s), 1.29 (6H, s),2.32 (2H, s), 2.41 (2H, q, J=7.5 Hz), 3.68 (2H, s), 6.83 (1H, d, J=8.1Hz), 7.19 (1H, d, J=8.1 Hz), 7.20-7.27 (1H, m), 7.37-7.42 (1H, m), 7.47(1H, t, J=7.5 Hz), 7.59 (4H, s), 7.62-7.68 (2H, m).

Example 579

[4121]N-[3′-(3,4,8,9-Tetrahydro-4,4,8,8-tetramethylfuro(2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-yl]formamide

[4122] Formic acid (0.5 mL) was treated dropwise with acetic anhydride(0.14 mL, 1.5 mmol) with cooling in ice, and stirred at the sametemperature for 1.5 hours. The resultant solution was added dropwise toa solution of3′-(3,4,8,9-tetrahydro-4,4,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-aminedihydrobromide (279 mg, 0.500 mmol) and sodium formate (75 mg, 1.1 mmol)in formic acid (0.5 mL), and the mixture was stirred at room temperaturefor 1.5 hours. The reaction mixture was added dropwise to a suspensionof sodium hydrogen carbonate (3.1 g, 37 mmol) in water-ethyl acetate,and the organic layer was separated, and the aqueous layer was extractedwith ethyl acetate. The combined organic layer was washed with brine,dried over sodium sulfate, filtered and concentrated under reducedpressure. The residue was crystallized from ethyl acetate-hexane toobtain the title compound (147 mg, yield: 69%).

[4123] Melting point: 197-199° C.

[4124]¹H NMR (CDCl₃) δ1.27 (6H, s), 1.29 (6H, s), 2.32 (2H, s), 3.69(2H, s), 6.84 (1H, d, J=8.4 Hz), 7.13 (1H, d, J=8.7 Hz), 7.20 (1H, d,J=8.4 Hz), 7.38-7.69 (8H, m), 8.38 (0.55H, d, J=1.8 Hz), 8.73 (0.45H, d,J=11.1 Hz).

Example 580

[4125]3′-(6-Hydroxy-4,4,8,8-tetramethyl-3,4,8,9-tetrahydrofurot2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-carboxylicacid ethyl ester

[4126] The title compound was obtained from1-(3-bromophenyl)-3,4,8,9-tetrahydro-4,4,8,8-tetramethyl-6-furo[2,3-h]isoquinolinoland 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid ethylester by the method similar to that in EXAMPLE 461. Yield: 52%.

[4127] Melting point: 214-217° C. (ethyl acetate-diethyl ether).

[4128]¹H NMR (CDCl₃) δ1.21 (6H, s), 1.28 (6H, s), 1.41 (3H, t, J=7.2Hz), 2.32 (2H, s), 3.60 (2H, s), 4.40 (2H, g, J=7.2 Hz), 6.73 (1H, s),7.38-7.54 (2H, m), 7.63-7.77 (2H, m), 7.68 (2H, d, J=8.4 Hz), 8.09 (2H,d, J=8.4 Hz).

Example 581

[4129][3′-[3,4,8,9-tetrahydro-4,4,8,8-tetramethyl-6-[[(trifluoromethyl)sulfonyl]oxy]furo[2,3-h]isoquinolin-1-yl][1,1′-biphenyl]-4-carboxylicacid ethyl ester

[4130] The title compound was obtained from3′-(6-hydroxy-4,4,8,8-tetramethyl-3,4,8,9-tetrahydrofuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-carboxylicacid ethyl ester by the method similar to that in EXAMPLE 95. Yield:97%.

[4131] Melting point: 147-149° C. (ethyl acetate-hexane).

[4132]¹H NMR (CDCl₃) δ1.29 (6H, s), 1.31 (6H, s), 1.42 (3H, t, J=7.2Hz), 2.38 (2H, s), 3.72 (2H, br s), 4.41 (2H, q, J=7.2 Hz), 7.10 (1H,s), 7.42-7.48 (1H, m), 7.50-7.57 (1H, m), 7.67-7.76 (4H, m), 8.12 (2H,d, J=8.1 Hz).

Example 582

[4133]3′-(3,4,8,9-Tetrahydro-4,4,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-carboxylicacid ethyl ester

[4134] The title compound was obtained from[3′-(3,4,8,9-tetrahydro-4,4,8,8-tetramethyl-6-[[(trifluoromethyl)sulfonylloxylfuro[2,3-h]isoquinolin-1-yl][1,1′-biphenyl]-4-carboxylicacid ethyl ester by the method similar to that in EXAMPLE 575. Yield:75%.

[4135] Melting point: 144-149° C. (hexane).

[4136]¹H NMR (CDCl₃) δ1.28 (6H, s), 1.29 (6H, s), 1.42 (3H, t, J=7.1Hz), 2.32 (2H, s), 3.69 (2H, s), 4.40 (2H, q, J=7.1 Hz), 6.84 (1H, d,J=3 8.4 Hz), 7.20 (1H, d, J=8.4 Hz), 7.47 (1H, dt, J=7.6, 1.7 Hz), 7.52(1H, td, J=7.6, 0.6 Hz), 7.67-7.76 (4H, m), 8.08-8.13 (2H, m).

Example 583

[4137]3′-(3,4,8,9-Tetrahydro-4,4,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-carboxylicacid

[4138] 1 M aqueous solution of sodium hydroxide (10 mL) was added to asuspension of3′-(3,4,8,9-tetrahydro-4,4,8,8-tetramethylfuro[2,3-h]lsoquinolin-1-yl)[1,1′-biphenyl]-4-carboxylicacid ethyl ester (1.30 g, 2.87 mmol) in ethanol (15 mi) and the mixturewas stirred at 70° C. for 45 minutes. the reaction mixture was cooledwith ice, treated dropwise with 1 M hydrochloric acid (10 mL), andextracted twice with chloroform. The combined organic layer was washedwith brine, combined with a small amount of methanol, dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas crystallized from chloroform-ethyl acetate to obtain the titlecompound (1.19 g, yield: 97%).

[4139] Melting point: 286-291° C.

[4140]¹H NMR (DMSO-d₆) δ1.19 (6H, s), 1.21 (6H, s), 2.28 (2H, s), 3.58(2H, s), 6.86 (1H, d, J=8.3 Hz), 7.24 (1H, d, J=8.3 Hz), 7.44 (1H, dt,J=7.6, 1.4 Hz), 7.58 (1H, t, J=7.6 Hz), 7.74 (1H, t, J=1.4 Hz),7.87-7.88 (3H, m), 8.03 (2H, d, J=8.4 Hz), 12.80-13.05 (1H, br).

Example 584

[4141]3′-(3,4,8,9-Tetrahydro-4,4,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-carboxamide

[4142] 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (125mg, 0.652 mmol) was added to a suspension of3′-(3,4,8,9-tetrahydro-4,4,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-carboxylicacid (213 mg, 0.501 mmol) and 1-hydroxy-1H-benzotriazole ammonium salt(92 mg, 0.60 mmol) in N,N-dimethylformamide (1 mL) and the mixture wasstirred at room temperature for 15 hours. Triethylamine (0.16 mL, 1.1mmol) was added to the resultant mixture and the mixture was stirred atroom temperature for 2 hours. The reaction mixture was combined withwater and extracted twice with ethyl acetate-tetrahydrofuran mixture.The combined organic layer was washed with brine, dried through sodiumsulfate-basic silica gel (eluting with ethyl acetate), and concentratedunder reduced pressure. The resultant solid was washed with ethylacetate-hexane to obtain the title compound (89.5 mg, yield: 42%).

[4143] Melting point: 284-296° C.

[4144]¹H NMR (DMSO-d₆) δ1.19 (6H, s), 1.21 (6H, s), 2.29 (2H, s), 3.58(2H, s), 6.86 (1H, d, J=8.1 Hz), 7.24 (1H, d, J=8.1 Hz), 7.36-7.45 (2H,m), 7.57 (1H, t, J=7.7 Hz), 7.73 (1H, t, J=1.5 Hz), 7.79 (2H, d, J=8.6Hz), 7.81-7.87 (1H, m), 7.97 (2H, d, J=8.6 Hz), 8.04 (1H, br s).

Example 585

[4145]N-Methyl-3′-(3,4,8,9-tetrahydro-4,4,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-carboxamide

[4146] The title compound was obtained from3′-(3,4,8,9-tetrahydro-4,4,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-4-carboxylicacid by the method similar to that in EXAMPLE 459. Yield: 70%.

[4147] Melting point: 242-244° C. (ethyl acetate-hexane).

[4148]¹H NMR (CDCl₃) δ1.27 (6H, s), 1.29 (6H, s), 2.32 (2H, s), 3.05(3H, d, J=4.8 Hz), 3.69 (2H, s), 6.15-6.25 (1H, m), 6.84 (1H, d, J=8.4Hz), 7.20 (1H, d, J=8.4 Hz), 7.46 (1H, dt, J=7.7, 1.5 Hz), 7.47-7.54(1H, m), 7.66-7.74 (4H, m), 7.83 (2H, d, J=8.4 Hz).

Example 586

[4149]3-(3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-6-(propylthio)furo[2,3-h]isoquinolin-1-yl)benzoicacid

[4150] A solution of an about 15:2 mixture of2,3-dihydro-2,2-dimethyl-5-(2-methyl-1-propenyl)-7-(propylthio)benzofuranand 2,3-dihydro-2,2-dimethyl-5-(2-methyl-1-propenyl)benzofuran obtainedin EXAMPLE 549 (3.10 g) and isopropyl 3-cyanobenzoate (1.83 g, 9.65mmol) in acetic acid (6 mL)-toluene (13 mL) was treated dropwise withconc. sulfuric acid (1.80 mL, 33.7 mmol) with cooling in ice, andstirred at 60° C. for 1.5 hours. Isopropyl alcohol (11.7 mL) was addeddropwlse to the mixture, and the mixture was heated under ref lux for 5hours. Ice water was poured into the reaction mixture, which wasneutralized with sodium hydrogen carbonate, and extracted twice withethyl acetate. The combined organic layer was washed with brine, driedover sodium sulfate, filtered and concentrated under reduced pressure.The residue was dissolved in N,N-dimethylformamide (20 mL), potassiumcarbonate (668 mg, 4.83 mmol) and 2-iodopropane (0.48 mL, 4.83 mmol)were added thereto, and the mixture was stirred at room temperature for15 hours. Water was poured into the reaction mixture, which wasextracted twice with ethyl acetate. The combined organic layer waswashed with water and brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was subjected to acolumn chromatography on a silica gel (hexane/ethyl acetate 10:1followed by 5:1) to obtain3-(3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-6-propylthiofuro(2,3-h]isoquinolin-1-yl)benzoicacid 1-methylethyl ester (1.00 g, yield: 22%) as an oil.

[4151] The resultant ester derivative (1.00 g, 2.15 mmol) was dissolvedin methanol (4 mL), 5 M aqueous solution of sodium 10 hydroxide (2 mL)was added thereto, and the mixture was stirred at room temperature for15 hours. The reaction mixture was adjusted at pH 4.5 with 5 Mhydrochloric acid, combined with sodium chloride, and extracted twicewith ethyl acetate. The combined organic layer was washed with brine,dried over magnesium sulfate, filtered and concentrated under reducedpressure. The residue was crystallized from ethyl acetate-diusopropylether to obtain the title compound (153 mg, yield: 17%).

[4152] Melting point: 206-208° C.

[4153]¹H NMR (CDCl₃) δ1.11 (3H, t, J=7.5 Hz), 1.25 (6H, s), 1.51 (3H,s), 1.74-1.86 (2H, m), 1.91 (3H s), 2.05-2.17 (2H, m), 2.83-3.04 (1H,m), 3.04 (2H, t, J=7.2 Hz), 3.30-3.50 (1H, m), 6.97 (1H, s), 7.60-7.72(2H, m), 8.00 (1H, d, J=3 7.5 Hz), 8.12 (1H, d, J=7.8 Hz).

Example 587

[4154]N-(2-Amino-1,1-dimethyl-2-oxoethyl)-3-(3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-6-(propylthio)furo[2,3-h]isoquinolin-1-yl)benzamide

[4155] 1-Hydroxy-1H-benzotriazole monohydrate (280 mg, 1.83 mmol),triethylamine (0.58 mL, 4.15 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (414 mg,2.16 mmol) were added to a solution of3-(3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-6-propylthiofurot2,3-h]isoquinolin-1-yl)benzoicacid (703 mg, 1.66 mmol) and 2-amino-2-methylpropanamide hydrochloride(254 mg, 1.83 mmol) in N,N-dimethylformamide (4 mL) and the mixture wasstirred at room temperature for 4 hours. Water was poured into thereaction mixture, which was extracted twice with ethyl acetate. Thecombined organic layer was washed with water and brine, dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresidue was subjected to a column chromatography on a basic silica gel(hexane/ethyl acetate 1:2 followed by ethyl acetate), and the resultantcrystals were washed with diisopropyl ether to obtain the title compound(478 mg, yield: 57%).

[4156] Melting point: 195-197° C.

[4157]¹H NMR (CDCl₃) δ1.05 (3H, t, J=7.2 Hz), 1.25 (6H, s), 1.30 (6H,s), 1.62-1.78 (2H, m), 1.71 (6H,8 s), 2.17 (2H, s), 2.68 (2H, s), 2.95(2H, t, J=7.3 Hz), 5.49 (1H, br s), 6.43 (1H, br s), 6.92 (1H, s), 6.96(1H, s), 7.43-7.52 (2H, m), 7.85-7.89 (2H, m).

Example 588

[4158]3,4,8,9-Tetrahydro-5,6-dimethoxy-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinolinehydrochloride

[4159] A solution of2,3-dihydro-6,7-dimethoxy-2,2-dimethyl-5-(2-methyl-1-propenyl)benzofuran(220 mg, 0.839 mmol) and benzonitrile (0.086 mL, 0.839 mmol) in aceticacid (0.4 mL)-toluene (1 mL) was treated dropwise with conc. sulfuricacid (0.11 mL, 2.10 mmol) with cooling in ice, and stirred at 80° C. for40 minutes. Ice water was poured into the reaction mixture, which waswashed with diisopropyl ether. The aqueous layer was neutralized withconc. aqueous ammonia, and extracted with ethyl acetate. The combinedorganic layer was washed twice with brine, dried over sodium sulfate,filtered and concentrated under reduced pressure. The residue wassubjected to a column chromatography on a basic silica gel (hexane/ethylacetate 10:1 followed by 5:1) to obtain a free base of the titlecompound.

[4160]¹H NMR (CDCl₃) δ1.25 (6H, s), 1.29 (6H, s), 2.13 (2H, s), 2.69(2H, s), 3.83 (3H, s), 3.99 (3H, s), 7.38 (5H, s).

[4161] This was dissolved in ethyl acetate, 4 M hydrogen chloride/ethylacetate solution was added thereto, and the mixture was concentratedunder reduced pressure crystallized from ethyl acetate diisopropyl etherto obtain the title compound (6 mg, yield: 2%).

[4162] Melting point: 155-157° C.

[4163] The compounds produced in EXAMPELS described above are indicatedin Tables 1 to 22 shown below. TABLE 1

ex. R¹ additive 1

— 2

— 3

— 4

— 5

— 6

— 7

— 8

— 9

— 10

— 11

HCl 12

HCl 13

HCl 14 CH₃ — 15

— 16

HCl 17

— 18

— 19

— 20

— 21

— 24

— 25

— 27

— 28

— 29

2HCl 30

— 31

— 32

— 33

— 34

— 35

— 36

— 37

— 38

— 39

— 40

— 41

— 42

— 43

— 44

— 45

— 46

— 47

— 48

—

[4164] TABLE 2

ex. R¹ additive 49

— 50

— 51

— 52

— 53

— 54

3HCl 55

— 56

— 57

HCl 58

— 59

— 60

— 61

— 62

— 63

— 64

2HCl 65

— 66

— 67

— 68

HCl 69

— 70

HCl 71

— 72

— 73

— 74

— 75

— 76

— 77

— 78

— 79

— 80

HCl 81

HCl

[4165] TABLE 3

addi- ex. R¹ tive 83

— 84

— 85

— 86

— 88

HCl 89

HCl 90

— 123

— 139

HCl 140

HCl 141

2HCl 142

2HCl 143

2HCl 144

2HCl 145

2HCl 146

2HCl 147

2HCl 148

— 149

— 150

2HCl 151

2HCl 152

— 153

— 154

— 155

HCl 156

HCl

[4166] TABLE 4

ex. R¹ additive 157

— 158

— 159

— 160

— 161

— 162

— 163

— 164

— 165

— 166

— 167

— 168

— 169

— 170

— 171

— 172

2HCl 173

2HCl 174

2HCl 175

— 176

— 177

HCl 178

— 179

— 180

— 181

— 182

— 183

HCl 247

HCl 248

— 249

— 250

— 251

— 252

— 253

— 254

— 255

2HCl

[4167] TABLE 5

ex. R¹ additive 256

— 257

2HCl 258

— 259

— 260

— 261

— 262

2HCl 263

— 264

HCl 265

HCl 266

— 267

— 268

HCl 269

— 270

— 271

— 272

— 273

— 274

HCl 275

— 276

— 277

HCl 278

2HCl 279

— 280

— 281

HCl 282

— 283

— 284

— 285

— 286

3HCl 287

2HCl 288

— 289

— 290

HCl 295

—

[4168] TABLE 6

ex. R¹ additive 296

— 297

HCl 299

2HCl 300

— 301

— 302

2HCl 303

— 304

— 306

HCl 307

HCl 308

HCl 309

HCl 310

HCl 311

HCl 312

HCl 313

HCl 314

HCl 315

HCl 316

HCl 317

HCl 318

HCl 319

— 320

HCl 321

— 322

HCl 323

— 324

HCl 325

HCl 326

HCl 327

— 328

— 329

— 330

— 331

— 332

— 333

— 334

— 335

— 336

2HCl

[4169] TABLE 7

addi- ex. R¹ tive 337

— 338

— 339

— 340

— 341

— 342

— 343

— 344

HCl 345

— 346

— 347

— 348

— 349

HCl 350

— 351

— 352

HCl 353

— 354

— 355

— 356

HCl 357

HCl 358

HCl 359

HCl 360

HCl 361

HCl 362

HCl 363

HCl 364

1.5 HCl 365

HCl 366

HCl 367

HCl 368

— 369

— 370

— 371

— 372

— 373

— 374

— 375

—

[4170] TABLE 8

addi- ex. R¹ tive 376

— 377

— 378

— 379

— 380

— 381

— 382

— 383

— 384

— 385

— 386

— 387

— 388

— 389

— 390

— 391

— 392

— 393

— 394

— 395

— 396

— 397

— 398

— 399

— 400

— 401

— 402

— 403

— 404

HCl 405

— 406

— 407

— 408

—

[4171] TABLE 9

ex. R¹ additive 409

— 410

— 411

— 412

— 413

— 414

— 415

— 419 —CO₂CH₃ — 420 —CO₂H HCl 421

— 422

— 423

— 431

— 432

— 433

— 434

—

[4172] TABLE 10

ex. R⁵ X additive 22 —C₂H₅ O — 91 —H O HBr 92 —H O — 95 —SO₂CF₃ O — 96—SO₂CF₃ O HCl 97 —H bond HCl 107 —C₂H₃ O HCl 136

O HCl 138

O HCl 186 —C₃H₇ O HCl 187

O — 188 —COCH₃ O HCl 189

O HCl 190 —C₄H₉ O — 191 —C₃H₇ O HCl 192

O — 193

O 2HCl 194

O — 195

O — 196

O — 197

O HCl 198

O — 199 —CO₂C₂H₅ O HCl 200

O — 201 —CH₂F O — 202

O — 203 —CH₂CO₂CH₃ O — 204 —CH₂CONH₂ O — 205 —CH₂CO₂H O HCl 206—CH₂CONHCH₃ O HCl 207 —CH₂CON(CH₃)₂ O — 208 —CH₂CH₂NH₂ O — 209 —CH₂CH₂OHO — 210 —CH₂CH₂F O — 211

O — 212

O HCl 213

S HCl 214 —CH₃ S HCl 215 —Cl bond HCl 217 —CH₃ NH HCl 218 —CH₃ NCH₃ 2HCl219 —C₂H₅ NH HCl 220 —H NH — 221 —CHO NH — 222 —COCH₃ NH — 223 —SO₂CH₃NH — 224 —COC₂H₅ NH — 225 —CO₂C₂H₅ NH — 226 —CH₂CO₂C₂H₅ NH — 227 —CONH₂NH — 228 —CONHCH₃ NH — 296 —C₂H₅ S HCl 305 —CH₃ bond HCl

[4173] TABLE 11

ex. R¹ R⁵ X additive 23

—C₂H₅O — 26

—C₂H₅ O — 82

—Ch₂H₅ O HCl 87

—CH₂H₅ O — 93

—H O HBr 94

—H O — 98

—H O — 99

—C₃H₇ O — 100

—CH₂CONH₂ O — 101

—CH₂H₅ O — 102

—C₂H₅ O HCl 103

—C₄H₉ O — 104

—C₄H₉ O HCl 105

—C₄H₉ O — 106

—C₂H₅ O — 124

—H O — 216

—Cl bond 2HCl

[4174] TABLE 12

ex. R⁴ R⁵ additive 113 —CH₂N(CH₃)₂ —H — 114 —CH₂N(CH₃)₂ —CH₃ — 115—CH₂N⁺(CH₃)₂I⁻ —CH₃ — 116

—CH₃ HCl 117 —CH₂N(CH₃)₂ —C₂H₅ — 118 —CH₂N(CH₃)₂ —COCH₃ — 119

—H — 120

—CH₃ 2HCl 121

—COCH₃ — 122

—COCH₃ 2HCl 132 —′C₃H₇ —H — 133 —′C₃H₇ —CH₃ HCl 134 —′C₃H₇ —C₂H₅ HCl 135—′C₃H₇ —COCH₃ HCl 137

—H — 229

—CH₃ — 230 —CHhd 2NH₂ —CH₃ — 231

—CH₃ — 232

—CH₃ — 233

—CH₃ — 234 —CH₂Br —CH₃ — 235 —CH₂OCH₃ —CH₂ HCl 236 —CH₂OC₂H₅ —CH₃ HCl237 —CH₂OH —CH₃ — 238 —CH₂F —CH₃ HCl 239 —CH₃ —CH₃ HCl 240 —CH₂CN —CH₃ —241 —CH₂CO₂C₂H₅ —CH₃ HCl 242 —CH₂CO₂H —CH₂ 243 —CH₂CONH₂ —CH₃ — 244—CH₂CONHCH₃ —CH₃ — 245

—H — 246 —CH₂OH —H —

[4175] TABLE 13

ex. R¹ R⁴ R⁵ additive 125

—H — 126

—C₂H₅ — 127

—C₂H₅ — 128

—C₂H₅ — 129

—C₂H₅ — 130

—C₂H₅ — 131

—C₂H₅ —

[4176] TABLE 14

ex. R¹ R² R³ R⁶ R⁷ R⁸ R⁹ additive 109

—CH₂Br —CH₃ —CH₃ —CH₃ —H —H — 184

—(CH₂)₅— —CH₃ —CH₃ —H —H HCl 185

—(CH₂)₅— —CH₃ —CH₃ —H —H HCl 416

—CH₃ —CH₃ —H —H —H —H — 417

—CH₃ —CH₃ —H —H —CH₃ —CH₃ — 418

—C₂H₅ —C₂H₅ —CH₃ —CH₃ —H —H HCl 424

—CH₃ —CH₃ —H —H —H —H — 425

—CH₃ —CH₃ —(CH₂)₄— —H —H — 426

—CH₃ —CH₃ —(CH₂)₄— —H —H — 427

—CH₃ —CH₃ —(CH₂)₄— —H —H — 428

—CH₃ —CH₃ —C₂H₅ —C₂H₅ —H —H HCl 429

—CH₃ —CH₃ —C₂H₅ —C₂H₅ —H —H HCl 430

—CH₃ —CH₃ —C₂H₅ —C₂H₅ —H —H HCl 435

—H —H —CH₃ —CH₃ —H —H HCl 436

—CH₃ —H —CH₃ —CH₃ —H —H — 437

—CH₃ —H —CH₃ —CH₃ —H —H — 438

—CO₂CH₃ —H —CH₃ —CH₃ —H —H —

[4177] TABLE 15

ex. R¹ R⁵ Y n additive 108

—CH₃ —CH(OH)— 0 — 110

—C₂H₅ —CH₂— 1 — 111

—CH₃ —CH₂— 1 — 112

—C₂H₅ —CH₂— 1 — 291

—CH₃ —CH(OH)— 0 HCl 292

—CH₃ —CH(OH)— 0 — 293

—CH₃ —CH(OH)— 0 HCl 294

—CH₃ —C(═O)— 0 —

[4178] TABLE 16

ad- ex. R¹ ditive 439

— 440

— 441

— 442

— 443

— 444

— 445

— 446

— 447

— 448

— 451

— 452

— 453

— 454

— 455

— 456

— 457

— 458

— 459

— 460

— 467

— 468

HCl 469

— 477

— 478

— 479

— 480

— 493

— 501

HCl 502

— 503

HCl 504

HCl 505

—

[4179] TABLE 17

ex. R¹ additive 506

HCl 507

HCl 508

HCl 509

HCl 510

HCl 511

HCl 512

HCl 513

— 514

HCl 515

HCl 516

— 517

— 518

— 519

— 520

— 521

HCl 522

— 523

HCl 524

— 525

HCl 526

— 527

HCl 528

— 529

— 530

— 531

— 532

— 533

— 534

HCl 535

— 536

HCl 537

— 538

— 539

— 540

— 541

2HCl 542

HCl 543

— 563

— 564

—

[4180] TABLE 18

ex. R¹ R⁵ X additive 449

—C₄H₉ O — 450

—C₄H₉ O — 461

—H O — 462

—SO₂CF₃ O — 463

—H bond — 464

—SO₂CF₃ O — 465

—H bond — 466

—H bond — 481

—C₂H₅ O — 482

—C₂H₅ O HCl 483

—C₂H₅ O — 484

—C₂H₅ O — 485

—C₂H₅ O — 486

—C₂H₅ O HCl 487

—C₂H₅ O — 488

—C₂H₅ O — 489

—C₂H₅ O — 490

—C₂H₅ O — 491

—C₂H₅ O — 492

—C₂H₅ O — 544

—C₂H₅ O — 545

—C₂H₅ O — 546

—C₂H₅ O 2HCl 547

—C₂H₅ O HCl 548

—C₂H₅ S⁺(—O) — 549

—C₃H₇ S — 550

—C₂H₅ S — 586

—C₃H₇ S — 587

—C₃H₇ S —

[4181] TABLE 19

ex. R² R³ R⁵ additive 470

—CH₃ —CH₃ — 471

—CH₃ —CH₃ — 472

—H —CH₃ — 473

—H —CH₃ — 474

—H —CH₃ — 475

— —CH₃ 2HCl 498

—CH₃ —C₂H₅ HCl 499

—CH₃ —C₂H₅ 2HCl 500

—CH₃ —C₂H₅ 2HCl

[4182] TABLE 20

ex. R¹ R² R³ Y n additive 476

—CH₃ —CH₃ —CH₂— 1 — 494

—CH₃ —CH₃ —CH(OH)— 0 — 495

—CH₃ —CH₃ —C(═O)— 0 — 496

—CH₃ —CH₃ —CH(OH)— 0 — 497

—CH₃ —CH₃ —C(═O)— 0 — 565

—H —H —C(CH₃)₂— 0 — 566

—H —H —C(CH₃)₂— 0 — 567

—H —H —C(CH₃)₂— 0 — 568 —CO₂C₂H₅ —H —H —C(CH₃)₂— 0 — 569

—H —H —C(CH₃)₂— 0 — 570

—H —H —C(CH₃)₂— 0 — 571

—H —H —C(CH₃)₂— 0 —

[4183] TABLE 21

ex. R¹ R⁴ R⁵ additive 551

—CH₂CN —CH₃ HCI 552

—CH₂CN —CH₃ HCI 553

—CH₂CN —CH₃ HCI 554

—CH₂CN —CH₃ — 555

—CH₂CN —CH₃ — 556

—CH₂CN —CH₃ HCI 557

—CH₂CN —CH₃ HCI 558

—CH₂CN —CH₃ — 559

—CH₂CN —CH₃ — 560

—CHO —CH₃ HCI 561

—CN —CH₃ — 562

—CH₂CN —C₂H₃ HCI 563

—OCH₃ —CH₃ HCI

[4184] TABLE 22

ex. R¹ R⁵ X additive 572

—H O — 573

—H O — 574

—SO₂CF₃ O — 575

—H bond — 576

—H bond 2HBr 577

—H bond — 578

—H bond — 579

—H bond — 580

—H O — 581

—SO₂CF₃ O — 582

—H bond — 583

—H bond — 584

—H bond — 585

—H bond —

Formulation Example 1

[4185] (1) Compound of Example 1 10.0 mg (2) Lactose 60.0 mg (3) Cornstarch 35.0 mg (4) Gelatin  3.0 mg (5) Magnesium stearate  2.0 mg

[4186] A mixture of 10.0 mg of the compound obtained in Example 1, 60.0mg of lactose and 35.0 mg of a corn starch was granulated using 0.03 mlof 10% aqueous solution of gelatin (3.0 mg as gelatin) through a 1 mmmesh sieve, dried at 40° C. and then sieved again. The resultant granulewas combined with 2.0 mg of magnesium stearate and then compressed. Theresultant core was coated with a sugar coating comprising sucrose,titanium dioxide, talc and gum arabic in an aqueous suspension. Theresultant coated tablet was imparted with a gloss with a beeswax toobtain a coated tablet.

Formulation Example 2

[4187] (1) Compound of Example 1 10.0 mg (2) Lactose 70.0 mg (3) Cornstarch 50.0 mg (4) Soluble starch  7.0 mg (5) Magnesium stearate  3.0 mg

[4188] 10.0 mg of the compound obtained in Example 1 and 3.0 mg ofmagnesium stearate were granulated using 0.07 mL of an aqueous solutionof a soluble starch (7.0 mg as soluble starch), dried, and then combinedwith 70.0 mg of lactose and 50.0 mg of a corn starch. The mixture wascompressed into a tablet.

Formulation Example 3

[4189] (1) Compound of Example 11  5.0 mg (2) Sodium chloride 20.0 mg(3) Distilled water to 2 mL

[4190] 5.0 mg of the compound obtained in Example 11 and 20.0 mg ofsodium chloride were dissolved in distilled water and water was thenadded to make the entire volume 2.0 mL. The solution was filtered, andfilled aseptically in a 2 mL ampoule. The ampoule was sterilized,sealed, whereby obtaining an injection solution.

Formulation Example 4

[4191] In a fluidized bed granulating drier (FD-5S, KK POWREXCorporation), 1500 g of the compound obtained in Example 1, 2025 g oflactose and 556.5 g of corn starch were mixed homogeneously, and then anaqueous solution in which 126 g of hydroxypropyl cellulose was dissolvedwas sprayed in the drier to effect a granulation, after which themixture was dried in the fluidized bed granulating drier. The resultantgranule was ground using a power mill and sieved through a 1.5 mmpunching screen to obtain a sized granule. 3927 g of this sized granulewas combined with 210 g of sodium croscarmellose and 63 g of magnesiumstearate, and mixed in a tumbler mixer to obtain a granule to becompacted into tablets. This granule was compacted into 300 mg tabletsusing a 6.5 mm frame in a tablet compacting machine. The resultant plaintablet was coated with a solution containing hydroxypropylmethylcellulose 2910 (TC-5) and macrogol 6000 dissolved therein and titaniumoxide and iron(III) oxide dispersed therein to obtain about 13500film-coated tablets each containing 100 mg whose composition is shownbelow. Tablet formulation: Content Composition (mg) (1) Compound ofExample 1 100.0 (2) Lactose 135.0 (3) Corn starch 37.1 (4) Sodiumcroscarmellose 15.0 (5) Hydroxypropyl cellulose 8.4 (6) Magnesiumstearate 4.5 Total (plain tablet) 300.0

[4192] Film-coated tablet composition: (1) Plain tablet (Film component)300.0 (2) Hydroxypropylmethyl cellulose 2910 7.455 (3) Macrogol 6000 1.5(4) Titanium oxide 1.0 (5) iron(III) oxide 0.015 Total 310.0

Formulation Example 5

[4193] According to the method described in Formulation Example 4, about13500 film-coated tablets having the formulation shown below eachcontaining 25 mg of the compound obtained in Example 1 were obtained.Tablet formulation: Content Composition (mg) (1) Compound of Example 125.0 (2) Lactose 210.0 (3) Corn starch 37.1 (4) Sodium croscarmellose15.0 (5) Hydroxypropyl cellulose 8.4 (6) Magnesium stearate 4.5 Total(plain tablet) 300.0

[4194] Film-coated formulation: (1) Plain tablet (Film components) 300.0(2) Hydroxypropyl cellulose 2910 7.485 (3) Macrogol 6000 1.5 (4)Titanium oxide 1.0 (5) iron(III) oxide 0.015 Total 310.0

Formulation Example 6

[4195] According to the method described in Formulation Example 4, about13500 film-coated tablets having the formulation shown below eachcontaining 5 mg of the compound obtained in Example 1 were obtained.Tablet formulation: Content Composition (mg) (1) Compound of Example 15.0 (2) Lactose 230.0 (3) Corn starch 37.1 (4) Sodium croscarmellose15.0 (5) Hydroxypropyl cellulose 8.4 (6) Magnesium stearate 4.5 Total(plain tablet) 300.0

[4196] Film-coated formulation: (1) Plain tablet (Film components) 300.0(2) Hydroxypropyl cellulose 2910 7.485 (3) Macrogol 6000 1.5 (4)Titanium oxide 1.0 (5) iron(III) oxide 0.015 Total 310.0

Formulation Example 7

[4197] According to the method described in Formulation Example 4, about13500 film-coated tablets having the formulation shown below eachcontaining 1 mg of the compound obtained in Example 1 were obtained.Tablet formulation: Content Composition (mg) (1) Compound of Example 11.0 (2) Lactose 234.0 (3) Corn starch 37.1 (4) Sodium croscarmellose15.0 (5) Hydroxypropyl cellulose 8.4 (6) Magnesium stearate 4.5 Total(plain tablet) 300.0

[4198] Film-coated formulation: (1) Plain tablet (Film components) 300.0(2) Hydroxypropyl cellulose 2910 7.485 (3) Macrogol 6000 1.5 (4)Titanium oxide 1.0 (5) iron(III) oxide 0.015 Total 310.0

Formulation Example 8

[4199] White vaseline  40 g Cetanol  10 g Bleached beeswax   5 gSorbitan sesquioleate   5 g LauroMOCROGOLD 0.5 g Methylp-hydroxybenzoate 0.1 g Propyl p-hydroxybenzoate 0.1 g Purified waterAppropriate

[4200] A topical wettable ointment having the composition shown above(100 g) was heated preliminarily at 70° C., and the solution wascombined with a solution which was obtained by dissolving 1 g of thecompound obtained in Example 1 in 20 mL of methanol with heating. At thesame temperature, the mixture was stirred with heating for 10 minutes toremove residual methanol, and then cooled to room temperature to obtaina wettable ointment.

Experiment Example 1 Assay of Phosphodiesterase IV-inhibiting Effect

[4201] (1) Human brain-derived phosphodiesterase 4D3-encoding genecloning

[4202] From a human brain cDNA library, a gene encodingphosphodiesterase 4D3 was cloned. Using 1 ng of brain QUICK-Clone™ cDNA(Clontech) as a template, each 20 pmol of a primer set:5′-CCACGATAGCTGCTCAAACAAGAG-3′ (SEQ. ID. No.1) and5′-ATAGAAACCCCAAGTCCAATAAAC-3′ (SEQ. ID. No.2) which was preparedreferring to the phosphodiesterase 4D3 gene base sequence reported byNemoz et al (FEBS Letters 384, 97-102, 1996) was added to effect a PCRby a MiniCycler™ (MJ RESEARCH) using TaKaRa EX Taq (TAKARA) (reactioncondition: 30 cycles of 0.5 minutes at 94° C., 0.5 minutes at 55° C. and4 minutes at 72° C.). The resultant PCR product was subjected to anagarose gel electrophoresis and an about 2.4 kb DNA fragment wasrecovered. This fragment was made blunt using a Pfu DNA polymerase(STRATAGENE) and then a phosphodiesterase 4D3 gene was cloned using ZeroBlunt PCR Cloning Kit (Invitrogen).

[4203] (2) Construction of E.coli expression vector

[4204] The plasmid obtained in Section (1) described above was digestedwith a restriction enzyme EcoRI (Takara) and subjected to an agarose gelelectrophoresis to recover an about 2.4 kb DNA fragment. This DNAfragment was digested with a restriction enzyme EcoRI (Takara) andligated with a pGEX4T-3 (Pharmacia) which had been treated with BAP(Takara). The resultant cDNA fragment had the base sequence representedby Sequence ID No.3, and the amino acid sequence represented by SequenceID No.4 was found to be encoded by the 74th to the 2092nd bases of thisbase sequence. This cDNA fragment was transformed into an E.coli BL21(FUNAKOSHI) using a ligation solution, whereby obtaining an Escherichiacoli BL21/pPDE4D3 capable of expressing the phosphodiesterase 4D3 gene.

[4205] (3) Expression of Recombinant Human Brain-derivedPhosphodiesterase 4D3 in Escherichia coli and purification thereof

[4206] Using the Escherichia colt BL21/pPDE4D3 obtained in Section (2)described above, a recombinant human brain-derived phosphodiesterase 4D3was obtained. The expression and purification of E. coli were inaccordance with the protocol attached to GST Gene Fusion System(Pharmacia). As a result, 34 mg of an about 76 kDa recombinant humanbrain-derived phodiesterase 4D3 was obtained as a target substance from1 L of the E. coli culture medium.

[4207] (4) Assay of phosphodiesterase IV-inhibiting effect

[4208] To a 96-well plate (OPTI plate, Packard), 10 μl of a buffersolution [0.5 M Tris-HCl (pH7.5), 83 mM MgCl₂, 17 mM EGTA], 10 μl of therecombinant human brain-derived phosphodiesterase 4D3 (0.0034 mg/mL)obtained in Section (1) described above, 65 μl of Ultrapure water, 5 μlof an inhibitor sample and 10 μl of [³H]cAMP were added and reacted for30 minutes at 30° C. After completing the reaction, 50 μl of SPA beadssolution [18 mg/mL Yttrium silicate beads, 18 mM ZnSO⁴] was added,allowed to stand at room temperature for about 20 minutes, and theradioactivity was counted using a scintillation counter (Topcount,Packard). The radioactivity observed in the presence of the recombinanthuman brain-derived phosphodiesterase 4D3 was 28245 cpm, which was incontrast with the control radioactivity (1020 cpm). This reactionunderwent the inhibition of the phosphodiesterase activity in thepresence of a phosphodiesterase IV inhibitor rolipram (BIOMOL ResearchLaboratories, Inc), and rolipram inhibited this enzymatic reaction by50% at about 100 nM. This assay system was employed to determine therecombinant human brain-derived phosphodiesterase-inhibiting effect(IC₅₀) of each inventive compound. The results are shown in Table 23.TABLE 23 PDE IV-inhibiting effect Example No. (IC₅₀ , nH) 39 19.4 459.36 149 40.1 157 82.0 179 124 180 123 263 13.7

Example 2 Inhibiting Effect on Antigen-induced Bronchoconstriction inGuinea Pigs

[4209] (1) Preparation of Rabbit Anti-ovalbumin (OA) Serum

[4210] A white rabbit (body weight: about 3 kg; New Zealand white:KITAYAMA LABES) was immunized by an intramuscular administration of 1.0mL of an emulsion of 0.5 mL of a 10% OA (Grade III, Sigma) solution and0.5 mL of Freund Complete Adjuvant (WAKO PURE CHEMICAL INDUSTRIES,LTD.). This procedure was conducted once every week repetitively 4 timesin total. One week after the final immunization, the whole blood wassampled. The blood sample was allowed to stand at room temperature for 1hour or longer, and then in a refrigeration room for a day. On thefollowing day, the serum fraction was isolated and centrifuged (3000rpm, 10 min.), and the supernatant was stored as an antiserum at −20° C.

[4211] (2) Antigen-induced Bronchoconstriction

[4212] The bronchoconstriction was measured by a modifiedKonzett-Rossler method. Each male Hartley guinea pig weighing 400 to 500g (NIPPON SLC, Shizuoka) was anesthetized with ether, treatedintravenously with 1.0 mL of a 8- to 16-fold diluted anti-OA serum, andsubjected to an experiment after 16 to 24 hours. Under an anesthesiawith urethane (1.2 g/kg ip) (Aldrich), a tracheal cannula was inserted,and gallamine triethiodide (1 mg/kg iv) (Sigma) was administered toarrest the spontaneous respiration. The animal was ventilatedartificially using an artificial respirator (Harvard model 683) at 70respirations/minutes, with each ventilation volume of 2 to 3 mL andinitial load of 10 cmH₂O, and the intratracheal pressure was measured atthe side arm of the tracheal cannula using a differential pressure typetransducer. Mepyramine maleate (1.0 mg/kg) (Sigma) and propranolol (1.0mg/kg) (Sigma) were administered intravenously 2 minutes after theadministration of gallamine triethiodide, and after further 2 minutesthe OA antigen (1.0 mg/kg) was administered intravenously to induce thebronchoconstriction.

[4213] A compound of Example was dissolved in 25% dimethylacetamide, 25%polyethylene glycol 400 and 50% physiological saline, and administeredintravenously 5 minutes before the antigen challenge at a dose of 1mg/kg. Percent inhibition was calculated based on the comparison with acontrol group (intravenous administration of a mixture of 25%dimethylacetamide, 25% polyethylene glycol 400 and 50% physiologicalsaline). The % inhibition by each inventive compound is shown in Table24. TABLE 24 % inhibition in Example No. bronchoconstriction 39 45 45 44149 58 157 57 179 46 180 57 263 59

Industrial Applicability

[4214] A furoisoquinoline derivative of the invention has an excellentphosphodiesterase (PDE) IV-inhibiting effect, and is useful as aprophylactic or therapeutic agent against an inflammation-induceddisease, such as bronchial asthma, chronic obstructive pulmonary disease(COPD), rheumatoid arthritis, autoimmune disease and diabetes, etc.

1 4 1 24 DNA Artificial Sequence primer 1 ccacgatagc tgctcaaaca agag 242 24 DNA Artificial Sequence primer 2 atagaaaccc caagtccaat aaac 24 32435 DNA Human CDS (74)..(2092) mat_peptide (74)..() 3 gaattcatctgtaaaaatca ctacatgtaa cgtaggagac aagaaaaata ttaatgacag 60 aagatctgcg aacatg atg cac gtg aat aat ttt ccc ttt aga agg cat 109 Met Met His Val AsnAsn Phe Pro Phe Arg Arg His 1 5 10 tcc tgg ata tgt ttt gat gtg gac aatggc aca tct gcg gga cgg agt 157 Ser Trp Ile Cys Phe Asp Val Asp Asn GlyThr Ser Ala Gly Arg Ser 15 20 25 ccc ttg gat ccc atg acc agc cca gga tccggg cta att ctc caa gca 205 Pro Leu Asp Pro Met Thr Ser Pro Gly Ser GlyLeu Ile Leu Gln Ala 30 35 40 aat ttt gtc cac agt caa cga cgg gag tcc ttcctg tat cga tcc gac 253 Asn Phe Val His Ser Gln Arg Arg Glu Ser Phe LeuTyr Arg Ser Asp 45 50 55 60 agc gat tat gac ctc tct cca aag tct atg tcccgg aac tcc tcc att 301 Ser Asp Tyr Asp Leu Ser Pro Lys Ser Met Ser ArgAsn Ser Ser Ile 65 70 75 gcc agt gat ata cac gga gat gac ttg att gtg actcca ttt gct cag 349 Ala Ser Asp Ile His Gly Asp Asp Leu Ile Val Thr ProPhe Ala Gln 80 85 90 gtc ttg gcc agt ctg cga act gta cga aac aac ttt gctgca tta act 397 Val Leu Ala Ser Leu Arg Thr Val Arg Asn Asn Phe Ala AlaLeu Thr 95 100 105 aat ttg caa gat cga gca cct agc aaa aga tca ccc atgtgc aac caa 445 Asn Leu Gln Asp Arg Ala Pro Ser Lys Arg Ser Pro Met CysAsn Gln 110 115 120 cca tcc atc aac aaa gcc acc ata aca gag gag gcc taccag aaa ctg 493 Pro Ser Ile Asn Lys Ala Thr Ile Thr Glu Glu Ala Tyr GlnLys Leu 125 130 135 140 gcc agc gag acc ctg gag gag ctg gac tgg tgt ctggac cag cta gag 541 Ala Ser Glu Thr Leu Glu Glu Leu Asp Trp Cys Leu AspGln Leu Glu 145 150 155 acc cta cag acc agg cac tcc gtc agt gag atg gcctcc aac aag ttt 589 Thr Leu Gln Thr Arg His Ser Val Ser Glu Met Ala SerAsn Lys Phe 160 165 170 aaa agg atg ctt aat cgg gag ctc acc cat ctc tctgaa atg agt cgg 637 Lys Arg Met Leu Asn Arg Glu Leu Thr His Leu Ser GluMet Ser Arg 175 180 185 tct gga aat caa gtg tca gag ttt ata tca aac acattc tta gat aag 685 Ser Gly Asn Gln Val Ser Glu Phe Ile Ser Asn Thr PheLeu Asp Lys 190 195 200 caa cat gaa gtg gaa att cct tct cca act cag aaggaa aag gag aaa 733 Gln His Glu Val Glu Ile Pro Ser Pro Thr Gln Lys GluLys Glu Lys 205 210 215 220 aag aaa aga cca atg tct cag atc agt gga gtcaag aaa ttg atg cac 781 Lys Lys Arg Pro Met Ser Gln Ile Ser Gly Val LysLys Leu Met His 225 230 235 agc tct agt ctg act aat tca agt atc cca aggttt gga gtt aaa act 829 Ser Ser Ser Leu Thr Asn Ser Ser Ile Pro Arg PheGly Val Lys Thr 240 245 250 gaa caa gaa gat gtc ctt gcc aag gaa cta gaagat gtg aac aaa tgg 877 Glu Gln Glu Asp Val Leu Ala Lys Glu Leu Glu AspVal Asn Lys Trp 255 260 265 ggt ctt cat gtt ttc aga ata gca gag ttg tctggt aac cgg ccc ttg 925 Gly Leu His Val Phe Arg Ile Ala Glu Leu Ser GlyAsn Arg Pro Leu 270 275 280 act gtt atc atg cac acc att ttt cag gaa cgggat tta tta aaa aca 973 Thr Val Ile Met His Thr Ile Phe Gln Glu Arg AspLeu Leu Lys Thr 285 290 295 300 ttt aaa att cca gta gat act tta att acatat ctt atg act ctc gaa 1021 Phe Lys Ile Pro Val Asp Thr Leu Ile Thr TyrLeu Met Thr Leu Glu 305 310 315 gac cat tac cat gct gat gtg gcc tat cacaac aat atc cat gct gca 1069 Asp His Tyr His Ala Asp Val Ala Tyr His AsnAsn Ile His Ala Ala 320 325 330 gat gtt gtc cag tct act cat gtg cta ttatct aca cct gct ttg gag 1117 Asp Val Val Gln Ser Thr His Val Leu Leu SerThr Pro Ala Leu Glu 335 340 345 gct gtg ttt aca gat ttg gag att ctt gcagca att ttt gcc agt gca 1165 Ala Val Phe Thr Asp Leu Glu Ile Leu Ala AlaIle Phe Ala Ser Ala 350 355 360 ata cat gat gta gat cat cct ggt gtg tccaat caa ttt ctg atc aat 1213 Ile His Asp Val Asp His Pro Gly Val Ser AsnGln Phe Leu Ile Asn 365 370 375 380 aca aac tct gaa ctt gcc ttg atg tacaat gat tcc tca gtc tta gag 1261 Thr Asn Ser Glu Leu Ala Leu Met Tyr AsnAsp Ser Ser Val Leu Glu 385 390 395 aac cat cat ttg gct gtg ggc ttt aaattg ctt cag gaa gaa aac tgt 1309 Asn His His Leu Ala Val Gly Phe Lys LeuLeu Gln Glu Glu Asn Cys 400 405 410 gac att ttc cag aat ttg acc aaa aaacaa aga caa tct tta agg aaa 1357 Asp Ile Phe Gln Asn Leu Thr Lys Lys GlnArg Gln Ser Leu Arg Lys 415 420 425 atg gtc att gac atc gta ctt gca acagat atg tca aaa cac atg aat 1405 Met Val Ile Asp Ile Val Leu Ala Thr AspMet Ser Lys His Met Asn 430 435 440 cta ctg gct gat ttg aag act atg gttgaa act aag aaa gtg aca agc 1453 Leu Leu Ala Asp Leu Lys Thr Met Val GluThr Lys Lys Val Thr Ser 445 450 455 460 tct gga gtt ctt ctt ctt gat aattat tcc gat agg att cag gtt ctt 1501 Ser Gly Val Leu Leu Leu Asp Asn TyrSer Asp Arg Ile Gln Val Leu 465 470 475 cag aat atg gtg cac tgt gca gatctg agc aac cca aca aag cct ctc 1549 Gln Asn Met Val His Cys Ala Asp LeuSer Asn Pro Thr Lys Pro Leu 480 485 490 cag ctg tac cgc cag tgg acg gaccgg ata atg gag gag ttc ttc cgc 1597 Gln Leu Tyr Arg Gln Trp Thr Asp ArgIle Met Glu Glu Phe Phe Arg 495 500 505 caa gga gac cga gag agg gaa cgtggc atg gag ata agc ccc atg tgt 1645 Gln Gly Asp Arg Glu Arg Glu Arg GlyMet Glu Ile Ser Pro Met Cys 510 515 520 gac aag cac aat gct tcc gtg gaaaaa tca cag gtg ggc ttc ata gac 1693 Asp Lys His Asn Ala Ser Val Glu LysSer Gln Val Gly Phe Ile Asp 525 530 535 540 tat att gtt cat ccc ctc tgggag aca tgg gca gac ctc gtc cac cct 1741 Tyr Ile Val His Pro Leu Trp GluThr Trp Ala Asp Leu Val His Pro 545 550 555 gac gcc cag gat att ttg gacact ttg gag gac aat cgt gaa tgg tac 1789 Asp Ala Gln Asp Ile Leu Asp ThrLeu Glu Asp Asn Arg Glu Trp Tyr 560 565 570 cag agc aca atc cct cag agcccc tct cct gca cct gat gac cca gag 1837 Gln Ser Thr Ile Pro Gln Ser ProSer Pro Ala Pro Asp Asp Pro Glu 575 580 585 gag ggc cgg cag ggt caa actgag aaa ttc cag ttt gaa cta act tta 1885 Glu Gly Arg Gln Gly Gln Thr GluLys Phe Gln Phe Glu Leu Thr Leu 590 595 600 gag gaa gat ggt gag tca gacacg gaa aag gac agt ggc agt caa gtg 1933 Glu Glu Asp Gly Glu Ser Asp ThrGlu Lys Asp Ser Gly Ser Gln Val 605 610 615 620 gaa gaa gac act agc tgcagt gac tcc aag act ctt tgt act caa gac 1981 Glu Glu Asp Thr Ser Cys SerAsp Ser Lys Thr Leu Cys Thr Gln Asp 625 630 635 tca gag tct act gaa attccc ctt gat gaa cag gtt gaa gag gag gca 2029 Ser Glu Ser Thr Glu Ile ProLeu Asp Glu Gln Val Glu Glu Glu Ala 640 645 650 gta ggg gaa gaa gag gaaagc cag cct gaa gcc tgt gtc ata gat gat 2077 Val Gly Glu Glu Glu Glu SerGln Pro Glu Ala Cys Val Ile Asp Asp 655 660 665 cgt tct cct gac acgtaacagtgca aaaactttca tgcctttttt ttttttaagt 2132 Arg Ser Pro Asp Thr 670agaaaaattg tttccaaagt gcatgtcaca tgccacaacc acggtcacac ctcactgtca 2192tctgccagga cgtttgttga acaaaactga ccttgactac tcagtccagc gctcaggaat 2252atcgtaacca gttttttcac ctccatgttc atccgagcaa ggtggacatc ttcacgaaca 2312gcgtttttaa caagatttca gcttggtaga gctgacaaag cagataaaat ctactccaaa 2372ttattttcaa gagagtgtga ctcatcaggc agcccaaaag tttattggac ttggggtttc 2432tat 2435 4 673 PRT human 4 Met Met His Val Asn Asn Phe Pro Phe Arg ArgHis Ser Trp Ile Cys 1 5 10 15 Phe Asp Val Asp Asn Gly Thr Ser Ala GlyArg Ser Pro Leu Asp Pro 20 25 30 Met Thr Ser Pro Gly Ser Gly Leu Ile LeuGln Ala Asn Phe Val His 35 40 45 Ser Gln Arg Arg Glu Ser Phe Leu Tyr ArgSer Asp Ser Asp Tyr Asp 50 55 60 Leu Ser Pro Lys Ser Met Ser Arg Asn SerSer Ile Ala Ser Asp Ile 65 70 75 80 His Gly Asp Asp Leu Ile Val Thr ProPhe Ala Gln Val Leu Ala Ser 85 90 95 Leu Arg Thr Val Arg Asn Asn Phe AlaAla Leu Thr Asn Leu Gln Asp 100 105 110 Arg Ala Pro Ser Lys Arg Ser ProMet Cys Asn Gln Pro Ser Ile Asn 115 120 125 Lys Ala Thr Ile Thr Glu GluAla Tyr Gln Lys Leu Ala Ser Glu Thr 130 135 140 Leu Glu Glu Leu Asp TrpCys Leu Asp Gln Leu Glu Thr Leu Gln Thr 145 150 155 160 Arg His Ser ValSer Glu Met Ala Ser Asn Lys Phe Lys Arg Met Leu 165 170 175 Asn Arg GluLeu Thr His Leu Ser Glu Met Ser Arg Ser Gly Asn Gln 180 185 190 Val SerGlu Phe Ile Ser Asn Thr Phe Leu Asp Lys Gln His Glu Val 195 200 205 GluIle Pro Ser Pro Thr Gln Lys Glu Lys Glu Lys Lys Lys Arg Pro 210 215 220Met Ser Gln Ile Ser Gly Val Lys Lys Leu Met His Ser Ser Ser Leu 225 230235 240 Thr Asn Ser Ser Ile Pro Arg Phe Gly Val Lys Thr Glu Gln Glu Asp245 250 255 Val Leu Ala Lys Glu Leu Glu Asp Val Asn Lys Trp Gly Leu HisVal 260 265 270 Phe Arg Ile Ala Glu Leu Ser Gly Asn Arg Pro Leu Thr ValIle Met 275 280 285 His Thr Ile Phe Gln Glu Arg Asp Leu Leu Lys Thr PheLys Ile Pro 290 295 300 Val Asp Thr Leu Ile Thr Tyr Leu Met Thr Leu GluAsp His Tyr His 305 310 315 320 Ala Asp Val Ala Tyr His Asn Asn Ile HisAla Ala Asp Val Val Gln 325 330 335 Ser Thr His Val Leu Leu Ser Thr ProAla Leu Glu Ala Val Phe Thr 340 345 350 Asp Leu Glu Ile Leu Ala Ala IlePhe Ala Ser Ala Ile His Asp Val 355 360 365 Asp His Pro Gly Val Ser AsnGln Phe Leu Ile Asn Thr Asn Ser Glu 370 375 380 Leu Ala Leu Met Tyr AsnAsp Ser Ser Val Leu Glu Asn His His Leu 385 390 395 400 Ala Val Gly PheLys Leu Leu Gln Glu Glu Asn Cys Asp Ile Phe Gln 405 410 415 Asn Leu ThrLys Lys Gln Arg Gln Ser Leu Arg Lys Met Val Ile Asp 420 425 430 Ile ValLeu Ala Thr Asp Met Ser Lys His Met Asn Leu Leu Ala Asp 435 440 445 LeuLys Thr Met Val Glu Thr Lys Lys Val Thr Ser Ser Gly Val Leu 450 455 460Leu Leu Asp Asn Tyr Ser Asp Arg Ile Gln Val Leu Gln Asn Met Val 465 470475 480 His Cys Ala Asp Leu Ser Asn Pro Thr Lys Pro Leu Gln Leu Tyr Arg485 490 495 Gln Trp Thr Asp Arg Ile Met Glu Glu Phe Phe Arg Gln Gly AspArg 500 505 510 Glu Arg Glu Arg Gly Met Glu Ile Ser Pro Met Cys Asp LysHis Asn 515 520 525 Ala Ser Val Glu Lys Ser Gln Val Gly Phe Ile Asp TyrIle Val His 530 535 540 Pro Leu Trp Glu Thr Trp Ala Asp Leu Val His ProAsp Ala Gln Asp 545 550 555 560 Ile Leu Asp Thr Leu Glu Asp Asn Arg GluTrp Tyr Gln Ser Thr Ile 565 570 575 Pro Gln Ser Pro Ser Pro Ala Pro AspAsp Pro Glu Glu Gly Arg Gln 580 585 590 Gly Gln Thr Glu Lys Phe Gln PheGlu Leu Thr Leu Glu Glu Asp Gly 595 600 605 Glu Ser Asp Thr Glu Lys AspSer Gly Ser Gln Val Glu Glu Asp Thr 610 615 620 Ser Cys Ser Asp Ser LysThr Leu Cys Thr Gln Asp Ser Glu Ser Thr 625 630 635 640 Glu Ile Pro LeuAsp Glu Gln Val Glu Glu Glu Ala Val Gly Glu Glu 645 650 655 Glu Glu SerGln Pro Glu Ala Cys Val Ile Asp Asp Arg Ser Pro Asp 660 665 670 Thr

1. A compound having a partial structure represented by Formula:

or its salt.
 2. The compound according to claim 1 represented byFormula:

(wherein R¹ is a hydrogen atom, optionally substituted hydrocarbongroup, optionally substituted heterocyclic group or optionallysubstituted amino group, each of R² and R³ is a hydrogen atom,optionally substituted hydrocarbon group or acyl group, and R² and R³may be taken together with the adjacent carbon atom to form anoptionally substituted 3- to 8-membered ring, R⁴ is a hydrogen atom,cyano group, optionally substituted hydrocarbon group, acyl group oroptionally substituted hydroxy group, R⁵ is (1) a hydrogen atom, (2) anoptionally substituted hydrocarbon group, (3) an acyl group, (4) anoptionally substituted heterocyclic group or (5) a halogen atom, each ofR⁶ and R⁷ is a hydrogen atom or optionally substituted hydrocarbongroup, and R⁶ and R⁷ are taken together with the adjacent carbon atom toform an optionally substituted 3- to 8-membered ring, each of R⁸ and R⁹is a hydrogen atom or optionally substituted hydrocarbon group, X is abond, oxygen atom, optionally oxidized sulfur atom or optionallysubstituted nitrogen atom, Y is an optionally substituted methylenegroup or carbonyl group, and n is 0 to 1).
 3. The compound according toclaim 2, wherein each of R² and R³ is a hydrogen atom, optionallysubstituted hydrocarbon group or acyl group, R² and R³ are takentogether with the adjacent carbon atom to form an optionally substituted3- to 8-membered homocyclic or heterocyclic group, R⁴ is a hydrogen atomor optionally substituted hydrocarbon group, each of R⁶ and R⁷ is ahydrogen atom or optionally substituted hydrocarbon group, R⁶ and R⁷ maybe taken together with the adjacent carbon atom to form an optionallysubstituted 3- to 8-membered homocyclic group, Y is methylene groupwhich may have a hydroxy group or carbonyl group.
 4. The compoundaccording to claim 2 wherein R¹ is any of the following (i) to (iii):(i) a C₁₋₆ alkyl group, C₂₋₆ alkenyl group, C₂₋₆ alkynyl group, C₃₋₆cycloalkyl group, C₃₋₆ cycloalkenyl group, C₆₋₁₄ aryl group or C₇₋₁₆aralkyl group which may have 1 to 5 substituent(s) selected from thegroup (hereinafter referred to as Substituent Group A) consisting of (1)a halogen atom, (2) a C₁₋₃ alkylenedioxy group, (3) a nitro group, (4) acyano group, (5) an optionally halogenated C₁₋₆ alkyl group, (6) anoptionally halogenated C₂₋₆ alkenyl group, (7) an optionally halogenatedC₂₋₆ alkynyl group, (8) a C₃₋₆ cycloalkyl group, (9) a C₆₋₁₄ aryl group,(10) an optionally halogenated C₁₋₆ alkoxy group, (11) an optionallyhalogenated C₁₋₆ alkylthio group, (12) a hydroxy group, (13) an aminogroup, (14) a mono-C₁₋₆ alkylamino group, (15) a mono-C₆₋₁₄ arylaminogroup, (16) a di-C₁₋₆ alkylamino group, (17) a di-C₆₋₁₄ arylamino group,(18) an acyl group selected from formyl, carboxy, carbamoyl, C₁₋₆ alkylcarbonyl, C₃₋₆ cycloalkyl-carbonyl, C₁₋₆ alkoxy-carbonyl, C₆₋₁₄aryl-carbonyl, C₇₋₁₆ aralkyl-carbonyl, C₆₋₁₄ aryloxy carbonyl, C₇₋₁₆aralkyloxy-carbonyl, (5- or 6-membered heterocycle having, in additionto carbon atoms, 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms)-carbonyl, mono-C₁₋₆ alkyl-carbamoyl, di-C₁₋₆alkyl-carbamoyl, C₆₋₁₄ aryl-carbamoyl, (5- or 6-membered heterocyclehaving, in addition to carbon atoms, 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms)-carbamoyl, C₁₋₆ alkyl-thiocarbonyl,C₃₋₆ cycloalkyl-thiocarbonyl, C₁₋₆ alkoxy-thiocarbonyl, C₆₋₁₄aryl-thiocarbonyl, C₇₋₁₆ aralkyl-thiocarbonyl, C₆₋₁₄aryloxy-thiocarbonyl, C₇₋₁₆ aralkyloxy-thiocarbonyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbonyl,thiocarbamoyl, mono-C₁₋₆ alkyl-thiocarbamoyl, di-C₁₋₆alkyl-thiocarbamoyl, C₆₋₁₄ aryl-thiocarbamoyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbamoyl,mono-C₁₋₆ alkylsulfamoyl, di-C₁₋₆ alkylsulfamoyl, C₆₋₁₄ arylsulfamoyl,C₁₋₆ alkylsulfonyl, C₆₋₁₄ arylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₄arylsulfinyl, sulfino, sulfo, C₁₋₆ alkoxysulfinyl, C₆₋₁₄aryloxysulfinyl, C₁₋₆ alkoxysulfonyl and C₆₋₁₄ aryloxysulfonyl, (19) anacylamino group selected from formylamino, C₁₋₆ alkyl-carboxamido, C₆₋₁₄aryl-carboxamido, C₁₋₆ alkoxy-carboxamido, C₁₋₆ alkylsulfonylamino andC₆₋₁₄ arylsulfonylamino, (20) an acyloxy group selected from C₁₋₆alkyl-carbonyloxy, C₆₋₁₄ aryl-carbonyloxy, C₁₋₆ alkoxy-carbonyloxy,mono-C₁₋₆ alkyl-carbamoyloxy, di-C₁₋₆ alkyl-carbamoyloxy, C₆₋₁₄aryl-carbamoyloxy and nicotinoyloxy, (21) a 4- to 14-memberedheterocyclic group having, in addition to carbon atoms, 1 to 4heteroatom(s) selected from nitrogen, sulfur and oxygen atoms, (22) aphosphono group, (23) a C₆₋₁₄ aryloxy group, (24) a di-C₁₋₆alkoxy-phosphoryl group, (25) a C₆₋₁₄ arylthio group, (26) a hydrazinogroup, (27) an imino group, (28) an oxo group, (29) an ureido group,(30) a C₁₋₆ alkyl-ureido group, (31) a di-C₁₋₆-alkyl-ureido group, (32)an oxide group and (33) a group formed by binding 2 or 3 groups selectedfrom (1) to (32) listed above, (ii) a 5- to 14-membered heterocyclicgroup having, in addition to carbon atoms, 1 to 4 heteroatom(s) selectedfrom nitrogen, sulfur and oxygen atoms which may have 1 to 5substituent(s) selected from Substituent Group A described above, (iii)an amino group which may have 1 or 2 substituent(s) selected from thefollowing (ia) to (iiia): (ia) a hydrogen atom, (iia) a C₁₋₆ alkylgroup, C₂₋₆ alkenyl group, C₂₋₆ alkynyl group, C₃₋₆ cycloalkyl group,C₃₋₆ cycloalkenyl group, C₆₋₁₄ aryl group or C₇₋₁₆ aralkyl group whichmay have 1 to 5 substituent(s) selected from Substituent Group Adescribed above, (iiia) an acyl group selected from formyl, carboxy,carbamoyl, C₁₋₆ alkyl-carbonyl, C₃₋₆ cycloalkyl-carbonyl, C₁₋₆alkoxy-carbonyl, C₆₋₁₄ aryl-carbonyl, C₇₋₁₆ aralkyl-carbonyl, C₆₋₁₄aryloxy carbonyl, C₇₋₁₆ aralkyloxy-carbonyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-carbonyl, mono-C₁₋₆alkyl-carbamoyl, di-C₁₋₆ alkyl carbamoyl, C₆₋₁₄ aryl-carbamoyl, (5- or6-membered heterocycle having, in addition to carbon atoms, 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygenatoms)-carbamoyl, C₁₋₆ alkyl-thiocarbonyl, C₃₋₆ cycloalkyl-thiocarbonyl,C₁₋₆ alkoxy-thiocarbonyl, C₆₋₁₄ aryl-thiocarbonyl, C₇₋₁₆aralkyl-thiocarbonyl, C₆₋₁₄ aryloxy-thiocarbonyl, C₇₋₁₆aralkyloxy-thiocarbonyl, (5- or 6-membered heterocycle having, inaddition to carbon atoms, 1 to 3 heteroatom(s) selected from nitrogen,sulfur and oxygen atoms)-thiocarbonyl, thiocarbamoyl, mono-C₁₋₆alkyl-thiocarbamoyl, di-C₁₋₆ alkyl-thiocarbamoyl, C₁₋₁₄aryl-thiocarbamoyl, (5- or 6-membered heterocycle having, in addition tocarbon atoms, 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms)-thiocarbamoyl, mono-C₁₋₆ alkylsulfamoyl, di-C₁₋₆alkylsulfamoyl, C₆₋₁₄ arylsulfamoyl, C₁₋₆ alkylsulfonyl, C₆₋₁₄arylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₄ arylsulfinyl, sulfino, sulfo,C₁₋₆ alkoxysulfinyl, C₆₋₁₄ aryloxysulfinyl, C₁₋₆ alkoxysulfonyl andC₆₋₁₄ aryloxysulfonyl, which may have 1 to 5 substituent(s) selectedfrom Substituent Group A described above; each of R² and R³ is any ofthe following (i) to (iii): (i) a hydrogen atom, (ii) a C₁₋₆ alkylgroup, C₂₋₆ alkenyl group, C₂₋₆ alkynyl group, C₃₋₆ cycloalkyl group,C₃₋₆ cycloalkenyl group, C₆₋₁₄ aryl group or C₇₋₁₆ aralkyl, group whichmay have 1 to 5 substituent(s) selected from Substituent Group Adescribed above, (iii) an acyl group selected from formyl, carboxy,carbamoyl, C₁₋₆ alkyl-carbonyl, C₃₋₆ cycloalkyl-carbonyl, C₁₋₆alkoxy-carbonyl, C₆₋₁₄ aryl-carbonyl, C₇₋₁₆ aralkyl-carbonyl, C₆₋₁₄aryloxy carbonyl, C₇₋₁₆ aralkyloxy-carbonyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-carbonyl, mono-C₁₋₆alkyl-carbamoyl, di-C₁₋₆ alkyl-carbamoyl, C₆₋₁₄ aryl-carbamoyl, (5- or6-membered heterocycle having, in addition to carbon atoms, 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygenatoms)-carbamoyl, C₁₋₆ alkyl-thiocarbonyl, C₃₋₆ cycloalkyl-thiocarbonyl,C₁₋₆ alkoxy-thiocarbonyl, C₆₋₁₄ aryl-thiocarbonyl, C₇₋₁₆aralkyl-thiocarbonyl, C₆₋₁₄ aryloxy-thiocarbonyl, C₇₋₁₆aralkyloxy-thiocarbonyl, (5- or 6-membered heterocycle having, inaddition to carbon atoms, 1 to 3 heteroatom(s) selected from nitrogen,sulfur and oxygen atoms)-thiocarbonyl, thiocarbamoyl, mono-C₁₋₆alkyl-thiocarbamoyl, di-C₁₋₆ alkyl-thiocarbamoyl, C₆₋₁₄aryl-thiocarbamoyl, (5- or 6-membered-heterocycle having, in addition tocarbon atoms, 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms)-thiocarbamoyl, mono-C₁₋₆ alkylsulfamoyl, di-C₁₋₆alkylsulfamoyl, C₆₋₁₄ arylsulfamoyl, C₁₋₆ alkylsulfonyl, C₆₋₁₄arylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₄ arylsulfinyl, sulfino, sulfo,C₁₋₆ alkoxysulfinyl, C₆₋₁₄ aryloxysulfinyl, C₁₋₆ alkoxysulfonyl andC₆₋₁₄ aryloxysulfonyl, which may have 1 to 5 substituent(s) selectedfrom Substituent Group A described above; R² and R³ may be takentogether with the adjacent carbon atom to form a C₃₋₈ cycloalkane or 3-to 8-membered heterocyclic ring which may have 1 to 3 substituent(s)selected from a C₁₋₆ alkyl, C₆₋₁₄ aryl, C₇₋₁₆ aralkyl, amino, mono-C₁₋₆alkylamino, mono-C₆₋₁₄ arylamino, di-C₁₋₆ alkylamino, di-C₆₋₁₄ arylaminoand 4- to 10-membered aromatic heterocyclic group; R⁴ is (i) a hydrogenatom, (ii) a cyano group, (iii) a C₁₋₆ alkyl group, C₂₋₆ alkenyl group,C₂₋₆ alkynyl group, C₃₋₆ cycloalkyl group, C₃₋₆ cycloalkenyl group,C₆₋₁₄ aryl group or C₇₋₁₆ aralkyl group which may have 1 to 5substituent(s) selected from Substituent Group A described above, (iv)an acyl group selected from formyl, carboxy, carbamoyl, C₁₋₆alkyl-carbonyl, C₃₋₆ cycloalkyl-carbonyl, C₁₋₆ alkoxy-carbonyl, C₆₋₁₄aryl-carbonyl, C₇₋₁₆ aralkyl-carbonyl, C₆₋₁₄ aryloxy-carbonyl, C₇₋₁₆aralkyloxy-carbonyl, (5- or 6-membered heterocycle having, in additionto carbon atoms, 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms)-carbonyl, mono-C₁₋₆ alkyl-carbamoyl, di-C₁₋₆alkyl-carbamoyl, C₆₋₁₄ aryl-carbamoyl, (5- or 6-membered heterocyclehaving, in addition to carbon atoms, 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms)-carbamoyl, C₁₋₆ alkyl-thiocarbonyl,C₃₋₆ cycloalkyl-thiocarbonyl, C₁₋₆ alkoxy-thiocarbonyl, C₆₋₁₄aryl-thiocarbonyl, C₇₋₁₆ aralkyl-thiocarbonyl, C₆₋₁₄aryloxy-thiocarbonyl, C₇₋₁₆ aralkyloxy-thiocarbonyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbonyl,thiocarbamoyl, mono-C₁₋₆ alkyl-thiocarbamoyl, di-C₁₋₆alkyl-thiocarbamoyl, C₆₋₁₄ aryl-thiocarbamoyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbamoyl,mono-C₁₋₆ alkylsulfamoyl, di-C₁₋₆ alkylsulfamoyl, C₆₋₁₄ arylsulfamoyl,C₁₋₆ alkylsulfonyl, C₆₋₁₄ arylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₄arylsulfinyl, sulfino, sulfo, C₁₋₆ alkoxysulfinyl, C₆₋₁₄aryloxysulfinyl, C₁₋₆ alkoxysulfonyl and C₆₋₁₄ aryloxysulfonyl, whichmay have 1 to 5 substituent(s) selected from Substituent Group Adescribed above, or, (v) a group represented by Formula: —OR⁴′ (R⁴′ is<1> a hydrogen atom, <2> a C₁₋₆ alkyl group, C₂₋₆ alkenyl group, C₂₋₆alkynyl group, C₃₋₆ cycloalkyl group, C₃₋₆ cycloalkenyl group, C₆₋₁₄aryl group or C₇₋₁₆ aralkyl group which may have 1 to 5 substituent(s)selected from Substituent Group A described above, or, <3> an acyl groupselected from formyl, carboxy, carbamoyl, C₁₋₆ alkyl-carbonyl, C₃₋₆cycloalkyl-carbonyl, C₁₋₆ alkoxy-carbonyl, C₆₋₁₄ aryl-carbonyl, C₇₋₁₆aralkyl-carbonyl, C₆₋₁₄ aryloxy-carbonyl, C₇₋₁₆ aralkyloxy-carbonyl, (5-or 6-membered heterocycle having, in addition to carbon atoms, 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygen atoms)-carbonyl,mono-C₁₋₆ alkyl-carbamoyl, di-C₁₋₆ alkyl-carbamoyl, C₆₋₁₄aryl-carbamoyl, (5- or 6-membered heterocycle having, in addition tocarbon atoms, 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms)-carbamoyl, C₁₋₆ alkyl-thiocarbonyl, C₃₋₆cycloalkyl-thiocarbonyl, C₁₋₆ alkoxy-thiocarbonyl, C₆₋₁₄aryl-thiocarbonyl, C₇₋₁₆ aralkyl-thiocarbonyl, C₆₋₁₄aryloxy-thiocarbonyl, C₇₋₁₆ aralkyloxy-thiocarbonyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbonyl,thiocarbamoyl, mono-C₁₋₆ alkyl-thiocarbamoyl, di-C₁₋₆alkyl-thiocarbamoyl, C₆₋₁₄ aryl-thiocarbamoyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbamoyl,mono-C₁₋₆ alkylsulfamoyl, di-C₁₋₆ alkylsulfamoyl, C₆₋₁₄ arylsulfamoyl,C₁₋₆ alkylsulfonyl, C₆₋₁₄ arylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₄arylsulfinyl, sulfino, sulfo, C₁₋₆ alkoxysulfinyl, C₆₋₁₄aryloxysulfinyl, C₁₋₆ alkoxysulfonyl and C₆₋₁₄ aryloxysulfonyl, whichmay have 1 to 5 substituent(s) selected from Substituent Group Adescribed above); R⁵ is any of the following (i) to (v): (i) a hydrogenatom, (ii) a C₁₋₆ alkyl group, C₂₋₆ alkenyl group, C₂₋₆ alkynyl group,C₃₋₆ cycloalkyl group, C₃₋₆ cycloalkenyl group, C₆₋₁₄ aryl group orC₇₋₁₆ aralkyl group which may have 1 to 5 substituent(s) selected fromSubstituent Group A described above, (iii) an acyl group selected fromformyl, carboxy, carbamoyl, C₁₋₆ alkyl-carbonyl, C₃₋₆cycloalkyl-carbonyl, C₁₋₆ alkoxy-carbonyl, C₆₋₁₄ aryl-carbonyl, C₇₋₁₆aralkyl-carbonyl, C₆₋₁₄ aryloxy-carbonyl, C₇₋₁₆ aralkyloxy-carbonyl, (5-or 6-membered heterocycle having, in addition to carbon atoms, 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygen atoms)-carbonyl,mono-C₁₋₆ alkyl-carbamoyl, di-C₁₋₆ alkyl-carbamoyl, C₆₋₁₄aryl-carbamoyl, (5- or 6-membered heterocycle having, in addition tocarbon atoms, 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms)-carbamoyl, C₁₋₆ alkyl-thiocarbonyl, C₃₋₆cycloalkyl-thiocarbonyl, C₁₋₆ alkoxy-thiocarbonyl, C₆₋₁₄aryl-thiocarbonyl, C₇₋₁₆ aralkyl-thiocarbonyl, C₆₋₁₄aryloxy-thiocarbonyl, C₇₋₁₆ aralkyloxy-thiocarbonyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbonyl,thiocarbamoyl, mono-C₁₋₆ alkyl-thiocarbamoyl, di-C₁₋₆alkyl-thiocarbamoyl, C₆₋₁₄ aryl-thiocarbamoyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbamoyl,mono-C₁₋₆ alkylsulfamoyl, di-C₁₋₆ alkylsulfamoyl, C₆₋₁₄ arylsulfamoyl,C₁₋₆ alkylsulfonyl, C₆₋₁₄ arylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₄arylsulfinyl, sulfino, sulfo, C₁₋₆ alkoxysulfinyl, C₆₋₁₄aryloxysulfinyl, C₁₋₆ alkoxysulfonyl and C₆₋₁₄ aryloxysulfonyl, whichmay have 1 to 5 substituent(s) selected from Substituent Group Adescribed above, (iv) a 5- to 14-membered heterocyclic ring containing 1to 4 heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms which may contain 1 to 5 substituent(s)selected from Substituent Group A described above, (v) a halogen atom;each of R⁶ and R⁷ is (i) a hydrogen atom, (ii) a C₁₋₆ alkyl group, C₂₋₆alkenyl group, C₂₋₆ alkynyl group, C₃₋₆ cycloalkyl group, C₃₋₆cycloalkenyl group, C₆₋₁₄ aryl group or C₇₋₁₆ aralkyl group which mayhave 1 to 5 substituent(s) selected from Substituent Group. A describedabove, R⁶ and R⁷ may be taken together with the adjacent carbon atom toform a C₃₋₈ cycloalkane or 3- to 8-membered heterocyclic ring which mayhave 1 to 3 substituent(s) selected from C₁₋₆ alkyl, C₆₋₁₄ aryl, C₇₋₁₆aralkyl, amino, mono-C₁₋₆ alkylamino, mono-C₆₋₁₄ arylamino, di-C₁₋₆alkylamino, di-C₆₋₁₄ arylamino and 4- to 10-membered aromaticheterocyclic group; each of R⁸ and R⁹ is (i) a hydrogen atom, (ii) aC₁₋₆ alkyl group, C₂₋₆ alkenyl group, C₂₋₆ alkynyl group, C₃₋₆cycloalkyl group, C₃₋₆ cycloalkenyl group, C₆₋₁₄ aryl group or C₇₋₁₆aralkyl group which may have 1 to 5 substituent(s) selected fromSubstituent Group A described above; X is (i) a bond, (ii) an oxygenatom, (iii) an optionally oxidized sulfur atom, (iv) a C₁₋₆ alkyl group,C₂₋₆ alkenyl group, C₂₋₆ alkynyl group, C₃₋₆ cycloalkyl group, C₃₋₆cycloalkenyl group, C₆₋₁₄ aryl group or C₇₋₁₆ aralkyl group which mayhave 1 to 5 substituent(s) selected from Substituent Group A describedabove, (v) a nitrogen atom having an acyl group selected from formyl,carboxy, carbamoyl, C₁₋₆ alkyl-carbonyl, C₃₋₆ cycloalkyl-carbonyl, C₁₋₆alkoxy-carbonyl, C₆₋₁₄ aryl-carbonyl, C₇₋₁₆ aralkyl-carbonyl, C₆₋₁₄aryloxy carbonyl, C₇₋₁₆ aralkyloxy-carbonyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-carbonyl, mono-C₁₋₆alkyl-carbamoyl, di-C₁₋₆ alkyl-carbamoyl, C₆₋₁₄ aryl-carbamoyl, (5- or6-membered heterocycle having, in addition to carbon atoms, 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygenatoms)-carbamoyl, C₁₋₆ alkyl-thiocarbonyl, C₃₋₆ cycloalkyl-thiocarbonyl,C₁₋₆ alkoxy-thiocarbonyl, C₆₋₁₄ aryl-thiocarbonyl, C₇₋₁₆aralkyl-thiocarbonyl, C₆₋₁₄ aryloxy-thiocarbonyl, C₇₋₁₆aralkyloxy-thiocarbonyl, (5- or 6-membered heterocycle having, inaddition to carbon atoms, 1 to 3 heteroatom(s) selected from nitrogen,sulfur and oxygen atoms)-thiocarbonyl, thiocarbamoyl, mono-C₁₋₆alkyl-thiocarbamoyl, di-C₁₋₆ alkyl-thiocarbamoyl, C₆₋₁₄aryl-thiocarbamoyl, (5- or 6-membered heterocycle having, in addition tocarbon atoms, 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms)-thiocarbamoyl, mono-C₁₋₆ alkylsulfamoyl, di-C₁₋₆alkylsulfamoyl, C₆₋₁₄ arylsulfamoyl, C₁₋₆ alkylsulfonyl, C₆₋₁₄arylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₄ arylsulfinyl, sulfino, sulfo,C₁₋₆ alkoxysulfinyl, C₆₋₁₄ aryloxysulfinyl, C₁₋₆ alkoxysulfonyl andC₆₋₁₄ aryloxysulfonyl, which may have 1 to 5 substituent(s) selectedfrom Substituent Group A described above, or, (vi) a 5- to 14-memberedheterocyclic group containing 1 to 4 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms in addition to carbon-atoms which maycontain 1 to 5 substituent(s) selected from Substituent Group Adescribed above; Y is <1> a methylene group which may havesubstituent(s) selected from Substituent Group A described above or <2>a carbonyl group; n is 0 or
 1. 5. The compound according to claim 2 or3, wherein R¹ is an optionally substituted aromatic hydrocarbon group,(2) an optionally substituted heterocyclic group, (3) an optionallysubstituted alicyclic hydrocarbon group or (4) a group represented byFormula: —L—R^(1a) wherein L is methylene, carbonyl or an optionallysubstituted nitrogen atom, R^(1a) is a hydrogen atom, optionallysubstituted aromatic group, optionally substituted hydroxy group oroptionally substituted amino group.
 6. The compound according to claim5, wherein R¹ is any of the following (i) to (iv): (i) a C₆₋₁₄ arylgroup which may have 1 to 5 substituent(s) selected from SubstituentGroup A described above, (ii) a 5- to 14-membered heterocyclic groupcontaining 1 to 4 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms in addition to carbon atoms which may contain 1 to 5substituent(s) selected from Substituent Group A described above, (iii)a C₃₋₆ cycloalkyl group which may have 1 to 5 substituent(s) selectedfrom Substituent Group A described above, (iv) a group represented byFormula: —L—R^(1a) wherein L is (a) a methylene, (b) a carbonyl or (c) anitrogen atom which may be substituted by the following (ia) to (iiia):(ia) a hydrogen atom, (iia) a C₁₋₆ alkyl group, C₂₋₆ alkenyl group, C₂₋₆alkynyl group, C₃₋₆ cycloalkyl group, C₃₋₆ cycloalkenyl group, C₆₋₁₄aryl group or C₇₋₁₆ aralkyl group which may have 1 to 5 substituent(s)selected from Substituent Group A described above, (iiia) an acyl groupselected from formyl, carboxy, carbamoyl, C₁₋₆ alkyl-carbonyl, C₃₋₆cycloalkyl-carbonyl, C₁₋₆ alkoxy-carbonyl, C₆₋₁₄ aryl-carbonyl, C₇₋₁₆aralkyl-carbonyl, C₆₋₁₄ aryloxy-carbonyl, C₇₋₁₆ aralkyloxy-carbonyl, (5-or 6-membered heterocycle having, in addition to carbon atoms, 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygen atoms)-carbonyl,mono-C₁₋₆ alkyl-carbamoyl, di-C₁₋₆ alkyl-carbamoyl, C₆₋₁₄aryl-carbamoyl, (5- or 6-membered heterocycle having, in addition tocarbon atoms, 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms)-carbamoyl, C₁₋₆ alkyl-thiocarbonyl, C₃₋₆cycloalkyl-thiocarbonyl, C₁₋₆ alkoxy-thiocarbonyl, C₆₋₁₄aryl-thiocarbonyl, C₇₋₁₆ aralkyl-thiocarbonyl, C₆₋₁₄aryloxy-thiocarbonyl, C₇₋₁₆ aralkyloxy-thiocarbonyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbonyl,thiocarbamoyl, mono-C₁₋₆ alkyl-thiocarbamoyl, di-C₁₋₆alkyl-thiocarbamoyl, C₆₋₁₄ aryl-thiocarbamoyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbamoyl,mono-C₁₋₆ alkylsulfamoyl, di-C₁₋₆ alkylsulfamoyl, C₆₋₁₄ arylsulfamoyl,C₁₋₆ alkylsulfonyl, C₆₋₁₄ arylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₄arylsulfinyl, sulfino, sulfo, C₁₋₆ alkoxysulfinyl, C₆₋₁₄aryloxysulfinyl, C₁₋₆ alkoxysulfonyl and C₆₋₁₄ aryloxysulfonyl, whichmay have 1 to 5 substituent(s) selected from Substituent Group Adescribed above, R^(1a) is (i) a hydrogen atom, (ii) <1> a C₆₋₁₄ arylgroup or <2> a 5- to 14-membered aromatic heterocyclic group containing1 to 4 heteroatom(s) selected from 1 or 2 kind(s) of nitrogen, sulfurand oxygen atoms in addition to carbon atoms, both of which may contain1 to 5 substituent(s) selected from Substituent Group A described above,(iii) a hydroxy group which may have C₁₋₆ alkyl group, C₂₋₆ alkenylgroup, C₂₋₆ alkynyl group, C₃₋₆ cycloalkyl group, C₃₋₆ cycloalkenylgroup, C₆₋₁₄ aryl group or C₇₋₁₆ aralkyl group which may have 1 to 5substituent(s) selected from Substituent Group A described above, (iv)an amino group which may be substituted by the following (ia) to (iiia):(ia) a hydrogen atom, (iia) a C₁₋₆ alkyl group, C₂₋₆ alkenyl group, C₂₋₆alkynyl group, C₃₋₆ cycloalkyl group, C₃₋₆ cycloalkenyl group, C₆₋₁₄aryl group or C₇₋₁₆ aralkyl group which may have 1 to 5 substituent(s)selected from Substituent Group A described above, (iiia) an acyl groupselected from formyl, carboxy, carbamoyl, C₁₋₆ alkyl-carbonyl, C₃₋₆cycloalkyl-carbonyl, C₁₋₆ alkoxy-carbonyl, C₆₋₁₄ aryl-carbonyl, C₇₋₁₆aralkyl-carbonyl, C₆₋₁₄ aryloxy-carbonyl, C₇₋₁₆ aralkyloxy-carbonyl, (5-or 6-membered heterocycle having, in addition to carbon atoms, 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygen atoms)-carbonyl,mono-C₁₋₆ alkyl-carbamoyl, di-C₁₋₆ alkyl-carbamoyl, C₆₋₁₄aryl-carbamoyl, (5- or 6-membered heterocycle having, in addition tocarbon atoms, 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms)-carbamoyl, C₁₋₆ alkylthiocarbonyl, C₃₋₆cycloalkyl-thiocarbonyl, C₁₋₆ alkoxy-thiocarbonyl, C₆₋₁₄aryl-thiocarbonyl, C₇₋₁₆ aralkyl-thiocarbonyl, C₆₋₁₄aryloxy-thiocarbonyl, C₇₋₁₆ aralkyloxy-thiocarbonyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbonyl,thiocarbamoyl, mono-C₁₋₆ alkyl-thiocarbamoyl, di-C₁₋₆alkyl-thiocarbamoyl, C₆₋₁₄ aryl-thiocarbamoyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbamoyl,,mono-C₁₋₆ alkylsulfamoyl, di-C₁₋₆ alkylsulfamoyl, C₆₋₁₄ arylsulfamoyl,C₁₋₆ alkylsulfonyl, C₆₋₁₄ arylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₄arylsulfinyl, sulfino, sulfo, C₁₋₆ alkoxysulfinyl, C₆₋₁₄aryloxysulfinyl, C₁₋₆ alkoxysulfonyl and C₆₋₁₄ aryloxysulfonyl.
 7. Thecompound according to claim 2 wherein R¹ is a group represented byFormula:

(wherein R^(1b) is a hydrogen atom or an optionally substitutedhydrocarbon group or optionally substituted heterocyclic group, Ring Dis an optionally substituted aromatic hydrocarbon ring or optionallysubstituted heterocyclic group, E is a bond, methylene, oxygen atom,optionally oxidized sulfur atom, optionally substituted nitrogen atom ora group represented by Formula: —CS—O—, —CO—O—, —S—CO—, —(CH₂)_(k)—CO—,—NR^(1C)—CO—(CH₂)_(m)—, —NR^(1C)—SO₂—(CH₂)_(m)—,—SO₂—NR^(1C)—(CH₂)_(m)—, —O—CS—NR^(1C)—(CH₂)_(m)—,—NR^(1C)—CO—NR^(1C)—(CH₂)_(m)—, —NR^(1C)—CO—(CH₂)_(m)—NR^(1C— wherein R)^(1C) is a hydrogen atom, optionally substituted alkyl group or acylgroup, k is 0 or 1, m is an integer of 0 to
 3. 8. The compoundaccording-to claim 7 wherein R^(1b) is (i) a C₁₋₆ alkyl group, C₂₋₆alkenyl group, C₂₋₆ alkynyl group, C₃₋₆ cycloalkyl group, C₃₋₆cycloalkenyl group, C₆₋₁₄ aryl group or C₇₋₁₆ aralkyl group which mayhave 1 to 5 substituent(s) selected from Substituent Group A describedabove, or, (ii) a 5- to 14-membered heterocyclic group containing 1 to 4heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms which may contain 1 to 5 substituent(s)selected from Substituent Group A-described above; Ring D is (i) a C₆₋₁₄aryl ring which may have 1 to 5 substituent(s) selected from SubstituentGroup A described above or (ii) a 5- to 14-membered heterocyclic ringcontaining 1 to 4 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms in addition to-carbon atoms which may contain 1 to 5substituent(s) selected from Substituent Group A described above; E isany of the following (i) to (viii): (i) a bond, (ii) methylene, (iii) anoxygen atom, (iv) an optionally oxidized sulfur atom, (v) a C₁₋₆alkyl-group, C₂₋₆ alkenyl group, C₂₋₆ alkynyl group, C₃₋₆ cycloalkylgroup, C₃₋₆ cycloalkenyl group, C₆₋₁₄ aryl group or C₇₋₁₆ aralkyl groupwhich may have 1 to 5 substituent(s) selected from Substituent Group Adescribed above, (vi) a nitrogen atom having an acyl group selected fromformyl, carboxy, carbamoyl, C₁₋₆ alkyl-carbonyl, C₃₋₆cycloalkyl-carbonyl, C₁₋₆ alkoxy-carbonyl, C₆₋₁₄ aryl-carbonyl, C₇₋₁₆aralkyl-carbonyl, C₆₋₁₄ aryloxy-carbonyl, C₇₋₁₆ aralkyloxy-carbonyl, (5-or 6-membered heterocycle having, in addition to carbon atoms, 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygen atoms)-carbonyl,mono-C₁₋₆ alkyl-carbamoyl, di-C₁₋₆ alkyl-carbamoyl, C₆₋₁₄aryl-carbamoyl, (5- or 6-membered heterocycle having, in addition tocarbon atoms, 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms)-carbamoyl, C₁₋₆ alkylthiocarbonyl, C₃₋₆cycloalkyl-thiocarbonyl, C₁₋₆ alkoxy-thiocarbonyl, C₆₋₁₄aryl-thiocarbonyl, C₇₋₁₆ aralkyl-thiocarbonyl, C₆₋₁₄aryloxy-thiocarbonyl, C₇₋₁₆ aralkyloxy-thiocarbonyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbonyl,thiocarbamoyl, mono-C₁₋₆ alkyl-thiocarbamoyl, di-C₁₋₆alkyl-thiocarbamoyl, C₆₋₁₄ aryl-thiocarbamoyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbamoyl,mono-C₁₋₆ alkylsulfamoyl, di-C₁₋₆ alkylsulfamoyl, C₆₋₁₄ arylsulfamoyl,C₁₋₆ alkylsulfonyl, C₆₋₁₄ arylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₄arylsulfinyl, sulfino, sulfo, C₁₋₆ alkoxysulfinyl, C₆₋₁₄aryloxysulfinyl, C₁₋₆ alkoxysulfonyl and C₆₋₁₄ aryloxysulfonyl, (vii) anitrogen atom having a 5- to 14-membered heterocyclic group containing 1to 4 heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms which may contain 1 to 5 substituent(s)selected from Substituent Group A described above; (viii) —CS—O—,—CO—O—, —S—CO—, —(CH₂)_(k)—CO—, —NR^(1C)—CO—(CH₂)_(m)—,—NR^(1C)—SO₂—(CH₂)_(m)—, —SO₂—NR^(1C)—(CH₂)_(m)—O—CS—NR^(1C)—(CH₂)_(m)—,—NR^(1C)—CO—NR^(1C)—(CH₂)_(m— or —NR) ^(1C)—CO—(CH₂)_(m)—NR^(1C)—wherein R^(1C) is (ia) a hydrogen atom, (iia) a C₁₋₆ alkyl group whichmay have 1 to 5 substituent(s) selected from Substituent Group Adescribed above, or, (iiia) an acyl group selected from formyl, carboxy,carbamoyl, C₁₋₆ alkyl-carbonyl, C₃₋₆ cycloalkyl-carbonyl, C₁₋₆alkoxy-carbonyl, C₆₋₁₄ aryl-carbonyl, C₇₋₁₆ aralkyl-carbonyl, C₆₋₁₄aryloxy-carbonyl, C₇₋₁₆ aralkyloxy-carbonyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-carbonyl, mono-C₁₋₆alkyl-carbamoyl, di-C₁₋₆ alkyl-carbamoyl, C₆₋₁₄ aryl-carbamoyl, (5- or6-membered heterocycle having, in addition to carbon atoms, 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygenatoms)-carbamoyl, C₁₋₆ alkyl-thiocarbonyl, C₃₋₆ cycloalkyl-thiocarbonyl,C₁₋₆ alkoxy-thiocarbonyl, C₆₋₁₄ aryl-thiocarbonyl, C₇₋₁₆aralkyl-thiocarbonyl, C₆₋₁₄ aryloxy-thiocarbonyl, C₇₋₁₆aralkyloxy-thiocarbonyl, (5- or 6-membered heterocycle having, inaddition to carbon atoms, 1 to 3 heteroatom(s) selected from nitrogen,sulfur and oxygen atoms)-thiocarbonyl, thiocarbamoyl, mono-C₁₋₆alkyl-thiocarbamoyl, di-C₁₋₆ alkyl-thiocarbamoyl, C₆₋₁₄aryl-thiocarbamoyl, (5- or 6-membered heterocycle having, in addition tocarbon atoms, 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms)-thiocarbamoyl, mono-C₁₋₆ alkylsulfamoyl. di-C₁₋₆alkylsulfamoyl, C₆₋₁₄ arylsulfamoyl, C₁₋₆ alkylsulfonyl, C₆₋₁₄arylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₄ arylsulfinyl, sulfino, sulfo,C₁₋₆ alkoxysulfinyl, C₆₋₁₄ aryloxysulfinyl, C₁₋₆ alkoxysulfonyl andC₆₋₁₄ aryloxysulfonyl, which may have 1 to 5 substituent(s) selectedfrom Substituent Group A described above; k is 0 or 1, m is an integerof 0 to 3).
 9. The compound according. to claim 7, wherein R^(1b) is;(1) a C₁₋₆ alkyl group [this C₁₋₆ alkyl group may have a substituentselected from a halogen atom, cyano, hydroxy, C₁₋₆ alkoxy-carbonyl,di-C₁₋₆ alkylamino, optionally.halogenated C₁₋₆ alkyl-carbonyl-amino,carboxy, carbamoyl, C₁₋₆ alkyl-carbamoyl, C₁₋₆ alkyl-carbonyloxy, C₁₋₆alkoxy-carbonyl-C₁₋₆ alkyl-carbamoyl, (5- to 6-membered heterocyclicring containing 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms in addition to carbon atoms)-C₁₋₆ alkyl-carbamoyl, C₁₋₆alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonylamino, (5- to6-membered heterocyclic ring containing 1 to 3 heteroatom(s) selectedfrom nitrogen, sulfur and oxygen atoms in addition to carbon atoms)-C₁₋₆alkylcarbamoyl, (5- to 6-membered heterocyclic ring containing 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms)-amino, sulfamoyl-C₆₋₁₄ aryl, carboxy-C₆₋₁₄aryl, C₁₋₆ alkoxy-carbonyl-C₆₋₁₄ aryl, carbamoyl-C₆₋₁₄ aryl, C₁₋₆alkyl-carbamoyl-C₆₋₁₄ aryl which may have a hydroxy and (4- to10-membered heterocyclic ring containing 1 to 3 heteroatom(s) selectedfrom nitrogen, sulfur and oxygen atoms in addition to carbonatoms)-carbamoyl-C₆₋₁₄ aryl], (2) a C₃₋₆ cycloalkyl group, (3) a C₆₋₁₄aryl group [this C₆₋₁₄ aryl group may have a substituent selected fromC₁₋₆ alkoxy, amino, carboxy, optionally halogenated C₁₋₆alkoxy-carbonylamino, C₁₋₆ alkoxy-carbonylamino, formylamino, ureido,C₁₋₆ alkylsulfonylamino, (C₁₋₆ alkyl)(C₁₋₆ alkylsulfonyl) amino, C₁₋₆alkoxy-carbonyl-C₁₋₆ alkylamino, optionally C₁₋₆ alkyl-esterifiedphosphono-C₁₋₆ alkylamino, mono- or di-C₁₋₆ alkyl-carbamoyl and C₇₋₁₆aralkyloxy-carbonylamino] or, (4) a 5- to 14-membered heterocyclic groupcontaining 1 to 4 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms in addition to carbon atoms [this heterocyclic group may besubstituted by 1 or 2 substituent(s) selected from a halogen atom, C₁₋₆alkyl, carboxy-C₁₋₆ alkyl, C₁₋₆ alkyl-carbonyloxy-C₁₋₆ alkyl, C₁₋₆alkoxy-carbonyl, C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkyl, C₁₋₆alkyl-carbamoyl-C₁₋₆ alkyl, carbamoyl, oxo and 4- to 10-memberedheterocyclic group containing 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms in addition to carbon atoms]; Ring Dis (i) a C₆₋₁₄ aryl ring or (ii) a 5- to 14-membered heterocyclic ringcontaining 1 to 4 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms in addition to carbon atoms; E is (i) a bond, (ii)methylene, (iii) O, (iv) S, (v) SO, (vi) SO₂, (vii) —NH—, (viii) —N(C₁₋₆alkyl)-, (ix) —N(C₁₋₆ alkyl-carbonyl)-, (x) —N(C₁₋₆ alkoxy-carbonyl)-,(xi) —N(C₁₋₆ alkyl-sulfonyl)-, (xii) —CO—O—, (xiii) —S—CO—, (xiv) agroup represented by Formula: —(CH₂)_(k)—CO wherein k is 0 or 1, (xv)—NR^(f)—CO—(CH₂)_(m1)— wherein R^(f) is a hydrogen atom or C₁₋₆alkoxy-carbonyl or C₁₋₆ alkyl group which may be substituted by aheterocyclic group containing 1 to 3 heteroatom(s) selected fromnitrogen, oxygen, sulfur atoms and the like in addition to carbon atoms,and m1 is an integer of 0 to 3, (xvi) a group represented by Formula—NR^(g)—SO₂—(CH₂)_(m2)— wherein R^(g) is a hydrogen atom or C₁₋₆alkyl-sulfonyl group and m2 is 0, (xvii) a group represented by Formula—SO₂—NR^(h)—(CH₂)_(m3)— wherein R^(h) is a hydrogen atom or C₁₋₆ alkylgroup and m3 is 0 or 1, (xviii) a group represented by Formula—O—CS—NR^(i)—(CH₂)_(m4)— wherein R^(i) is a hydrogen atom or C₁₋₆ alkylgroup and m4 is 0 or 1, (xix) a group represented by Formula—NR^(j)—CO—NR^(k)—(CH₂)_(m5)— wherein R^(j) is a hydrogen atom or C₁₋₆alkyl group, R^(k) is a hydrogen atom or C₁₋₆ alkyl group and m5 is 0 or1, (xx) a group represented by Formula —NR^(L)—CO—CH₂—(CH₂)_(m6)—NR^(m)—wherein R^(L) is a hydrogen atom or C₁₋₆ alkyl group, R^(m) is ahydrogen atom or C₁₋₆ alkyl group and m6 is 0 or
 1. 10. The compoundaccording to claim 2 wherein R¹ is a group represented by Formula:

wherein Hal is a halogen atom, Ring D is defined as described in claim7.
 11. The compound according to claim 2, wherein R¹ is a grouprepresented by Formula:

wherein each symbol is defined as described in claim 7 or a grouprepresented by Formula:

wherein each symbol is defined as described in claim 7, each of R² andR³ is a hydrogen atom or optionally substituted hydrocarbon group, andR² and R³ may be taken together with the adjacent carbon atom to form anoptionally substituted 3- to 8-membered ring, R⁴ is a hydrogen atom,cyano group, optionally substituted hydrocarbon group, acyl group or agroup represented by Formula: —OR⁴′ wherein R⁴′ is a hydrogen atom,optionally substituted hydrocarbon group or acyl.group, R⁵ is anoptionally substituted hydrocarbon group, each of R⁶ and R⁷ is anoptionally substituted hydrocarbon group, R⁶ and R⁷ may be takentogether with the adjacent carbon atom to form an optionally substituted3- to 8-membered ring, each of R⁸ and R⁹ is a hydrogen atom, X is anoxygen atom or an optionally oxidized sulfur atom, Y is methylene whichmay have 1 or 2 C₁₋₆ alkyl group(s) and n is 0 or
 1. 12. The compoundaccording to claim 2, wherein R¹ is, (i) a C₆₋₁₄ aryl group which mayhave 1 to 3 substituent(s) selected from the following (1) to (23): (1)a halogen atom, (2) a nitro group, (3) a C₁₋₆ alkyl group [this C₁₋₆alkyl group may have a substituent selected from a halogen atom, cyano,carbamoyl, C₁₋₆ alkyl-carbamoyl, C₁₋₆ alkyl-carbonyloxy, C₁₋₆alkoxy-carbonyl-C₁₋₆ alkyl-carbamoyl, (5- or 6-membered heterocyclicring containing 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms in addition to carbon atoms) —C₁₋₆ alkyl-carbamoyl, C₁₋₆alkylsulfonylamino, C₁₋₆ alkoxy-carbonyl and carboxy], (4) a C₃₋₆cycloalkyl group, (5) a C₆₋₁₄ aryl group [this C₆₋₁₄ aryl group may havea substituent selected from amino, carboxy, C₁₋₆ alkoxy-carbonyl,carbamoyl, mono- or di-C₁₋₆ alkylcarbamoyl, formylamino, C₁₋₆alkyl-carbonylamino which may have a halogen atom or carboxy, C₆₋₁₄aryl-carbonylamino, C₁₋₆ alkoxy-carbonylamino, ureido, mono- or di-C₁₋₆alkylureido, C₁₋₆ alkylsulfonylamino, (C₁₋₆ alkyl) (C₁₋₆ alkylsulfonyl)amino, (C₁₋₆ alkyl) (C₁₋₆ alkyl-carbonyl) amino, C₁₋₆alkoxy-carbonyl-C₁₋₆ alkylamino, C₆₋₁₄ aralkyloxy-carbonylamino, C₁₋₆alkyl-carbonylamino-C₁₋₆ alkyl-carbonylamino, C₁₋₆ alkylthio-C₁₋₆alkyl-carbonylamino, C₁₋₆ alkyl-sulfinyl-C₁₋₆ alkyl-carbonylamino, C₁₋₆alkyl-sulfonyl-C₁₋₆ alkyl-carbonylamino, C₆₋₁₄ aryloxy-carbonylamino andhydroxy-C₁₋₆ alkyl-carbamoyl], (6) a C₁₋₆ alkoxy group which may have ahalogen atom or C₁₋₆ alkoxy-C₆₋₁₄ aryl, (7) a C₆₋₁₄ aryloxy group, (8) aC₁₋₆ alkylthio group which may have a carbamoyl, (9) a C₁₋₆alkylsulfinyl group which may have a carbamoyl, (10) a C₆₋₁₄ arylthiogroup, (11) a hydroxy group, (12) a 5- to 14-membered heterocyclic groupcontaining 1 to 4 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms [this heterocyclic group may have a substituent selectedfrom oxo, carboxy-C₁₋₆ alkyl, C₁₋₆ alkyl-carbonyloxy-C₁₋₆ alkyl, C₁₋₆alkyl, C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkyl, C₁₋₆ alkoxy-carbonyl,carbamoyl-C₁₋₆ alkyl and C₁₋₆ alkyl-carbamoyl-C₁₋₆ alkyl], (13) acarboxy group, (14) a group represented by Formula: —CO—Hal (wherein Halis a halogen atom), (15) a C₁₋₆ alkyl-carbonyl group, (16) a C₁₋₆alkyl-sulfonyl group, (17) a C₁₋₆ alkoxy-carbonyl group, (18) asulfamoyl group [this sulfamoyl group may have 1 or 2 substituent(s)selected from C₁₋₆ alkyl, carbamoyl-C₁₋₆ alkyl, C₁₋₆alkoxy-carbonyl-C₁₋₆ alkyl, (5- to 8-membered heterocyclic ring whichmay have an oxo group)-C₁₋₆ alkyl and C₁₋₆ alkyl-carbonylamino-C₆₋₁₄aryl], (19) a group represented by Formula: —NR^(a)R^(b) [each of R^(a)and R^(b) is (i) a hydrogen atom, (ii) a C₁₋₆ alkyl, (iii) (5- or6-membered heterocyclic ring containing 1 to 3 heteroatom(s) selectedfrom nitrogen, sulfur and oxygen atoms in addition to carbon atoms)-C₁₋₆alkyl, (iv) a C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkyl, (v) a di-C₁₋₆alkylamino-methylene-sulfamoyl-C₁₋₆ alkyl, (vi) a carbamoyl-C₁₋₆ alkyl,(vii) a sulfamoyl-C₁₋₆ alkyl, (viii) a C₁₋₆ alkyl-sulfonyl, (ix) a C₁₋₆alkoxy-carbonyl, (x) a di-C₁₋₆ alkoxy-carbonyl-C₂₋₆ alkenyl, (xi) aC₆₋₁₄ aryl, (xii) a 5- or 6-membered heterocyclic group containing 1 to3 heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms [this 5- or 6-membered heterocyclic group mayhave a substituent selected from amino, C₁₋₆ alkyl-carboxamido and C₁₋₆alkyl-sulfonylamino], (xiii) an optionally halogenated C₁₋₆alkyl-carbonyl, (xiv) a C₁₋₆ alkylthio-C₁₋₆ alkyl-carbonyl, (xv) a C₁₋₆alkylsulfinyl-C₁₋₆ alkyl-carbonyl, (xvi) a C₁₋₆ alkylsulfonyl-C₁₋₆alkyl-carbonyl, (xvii) an amino-C₁₋₆ alkyl-carbonyl, (xviii) anoptionally halogenated C₁₋₆ alkyl-carbonyl-amino-C₁₋₆ alkyl-carbonyl,(xix) a C₆₋₁₄ aryl-carbonyl, (xx) a carboxy-C₆₋₁₄ aryl-carbonyl, (xxi)an optionally C₁₋₆ alkyl-esterified phosphono-C₁₋₆ alkyl-C₆₋₁₄aryl-carbonyl, (xxii) (5- or 6-membered heterocyclic ring containing 1to 3 heteroatom(s) selected from nitrogen, sulfur and oxygen atoms Inaddition to carbon atoms which may have a halogen atom, oxy or a C₁₋₆alkoxy-carbonyl)-carbonyl, (xxiii) (5- or 6-membered heterocyclic ringcontaining 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms in addition to carbon atoms)-C₁₋₆ alkyl-carbonyl, (xxiv) aC₆₋₁₄ aryl-oxy-carbonyl, (xxv) a carboxy-C₁₋₆ alkyl, (xxvi) a carbamoyl,(xxvii) an optionally halogenated C₁₋₆ alkylcarbamoyl, (xxviii) a C₆₋₁₄arylcarbamoyl which may have a C₁₋₆ alkyl-carbonylamino, (xxix) (5- or6-membered heterocyclic ring containing 1 to 3 heteroatom(s) selectedfrom nitrogen, sulfur and oxygen atoms in addition to carbonatoms)-carbamoyl, (xxx) a C₂₋₆ alkenyl-carbonyl, (xxxi) a (5- or6-membered heterocyclic ring containing 1 to 3 heteroatom(s) selectedfrom nitrogen, sulfur and oxygen atoms in addition to carbon atoms whichmay have an oxo group)-amino-C₁₋₆ alkyl-carbonyl, (xxxii) a (5- or6-membered heterocyclic ring containing 1 to 3 heteroatom(s) selectedfrom nitrogen, sulfur and oxygen atoms in addition to carbon atoms whichmay have an oxo group)(C₁₋₆ alkyl) amino-C₁₋₆ alkyl-carbonyl, (xxxiii) a(5- or 6-membered heterocyclic ring containing 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms in addition to carbonatoms which may have an oxo group)(C₁₋₆ alkylcarbonyl) amino-C₁₋₆alkyl-carbonyl, (xxxiv) a C₁₋₆ alkylthio-C₁₋₆ alkylcarbonyl (sulfur atommay be oxidized), (xxxv) an optionally halogenated C₁₋₆ alkylsulfonyl,(xxxvi) a sulfamoyl or (xxxvii) a C₁₋₆ alkylsulfamoyl], (20) a grouprepresented by Formula: —C(═O)NR^(c)R^(d) [each of R^(c) and R⁴ is (i) ahydrogen atom, (ii) a C₁₋₆ alkyl, (iii) a (5- or 6-membered heterocyclicring containing 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms in addition to carbon atoms)-C₁₋₆ alkyl, (iv) acarboxy-C₁₋₆alkyl, (v) a C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkyl, (vi) a di-C₁₋₆alkylamino-C₁₋₆ alkyl, (vii) a carbamoyl-C₁₋₆ alkyl, (viii) a C₁₋₆alkylcarbamoyl-C₁₋₆ alkyl, (ix) (5- or 6-membered heterocyclic groupcontaining 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms in addition to carbon atoms)-C₁₋₆ alkylcarbamoyl-C₁₋₆alkyl, (x) (5- or 6-membered heterocyclic group containing 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms)-amino-C₁₋₆ alkyl, (xi) a sulfamoyl-C₆₋₁₄aryl-C₁₋₆ alkyl, (xii) a C₆₋₁₄ aryl which may have a C₁₋₆ alkoxy, (xiii)an optionally C₁₋₆ alkyl-esterified phosphono-C₁₋₆ alkyl-C₆₋₁₄ aryl,(xiv) a 4- to 10-membered heterocyclic ring containing 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms [this 4- to 10-membered heterocyclic group mayhave 1 to 2 substituent(s) selected from a halogen atom, C₁₋₆ alkyl andoxo], (xv) a C₆₋₁₄ aryl-carbamoyl-C₁₋₆ alkyl, (xvi) a hydroxy-C₁₋₆ alkylor (xvii) a (5- or 6-membered heterocyclic ring containing 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms which may have a oxo group)-carbamoyl-C₁₋₆alkyl], (21) a cyano group, (22) a mono- or di-C₁₋₆ alkylcarbamoylthiogroup, (23) a mono- or di-C₁₋₆ alkylthiocarbamoyloxy group; (ii) a 5- to14-membered heterocyclic group containing 1 to 4 heteroatom(s) selectedfrom nitrogen, sulfur and oxygen atoms in addition to carbon atoms whichmay contain 1 to 3 substituent(s) selected from the following (1) to(8): (1) a halogen atom, (2) a C₁₋₆ alkyl group [this alkyl may have asubstituent selected from carboxy, C₁₋₆ alkoxy, C₁₋₆ alkoxy-carbonyl,mono- C₁₋₆ alkyl-amino, di-C₁₋₆ alkyl-amino, carbamoyl, C₁₋₆alkyl-carbamoyl which may have a hydroxy, 4- to 10-membered heterocyclicgroup containing 1 to 3 heteroatom(s) selected from nitrogen, sulfur.andoxygen atoms in addition to carbon atoms which may have oxo, (4- to10-membered heterocyclic ring containing 1 to 3 heteroatom(s) selectedfrom nitrogen, sulfur and oxygen atoms in addition to carbonatoms)-carbamoyl, carbamoyl-C₁₋₆ alkyl-carbamoyl], (3) a C₁₋₆ alkoxygroup, (4) a C₆₋₁₄ aryl group, (5) a C₇₋₁₆ aralkyl group [this C₇₋₁₆aralkyl group may have a substituent selected from carboxy, C₁₋₆alkoxy-carbonyl, carbamoyl, C₁₋₆ alkyl-carbamoyl which may have ahydroxy, (4- to 10-membered heterocyclic ring containing 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms)-carbamoyl], (6) a 4- to 10-memberedheterocyclic group containing 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms in addition to carbon atoms [this 4-to 10-membered heterocyclic group may have a substituent selected from aC₁₋₆ alkyl, C₁₋₆ alkoxy-carbonyl, carbamoyl, oxo, 4- to 10-memberedheterocyclic group containing 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms in addition to carbon atoms], (7) anoxo group, (8) an oxide group; (iii) a C₃₋₆ cycloalkyl group; or, (iv) agroup represented by Formula: —L′—R^(1a)′ (L′ is methylene, carbonyl oran optionally substituted nitrogen atom, R^(1a)′ is (1) a hydrogen atom,(2) a C₆₋₁₄ aryl group which may have 1 to 5 substituent(s) selectedfrom a C₁₋₆ alkyl and C₁₋₆ alkoxy, (3) a hydroxy group which may besubstituted by a C₁₋₆ alkyl group, (4) a C₁₋₆ alkyl-amino group whichmay be substituted by a 4- to 10-membered heterocyclic ring containing-1to 3 heteroatom(s) selected from nitrogen, oxygen and sulfur atoms inaddition to carbon atoms, (6) a C₆₋₁₄ aryl-amino group or (7) a (4- to10-membered heterocyclic ring containing 1 to 3 heteroatom(s) selectedfrom nitrogen, oxygen and sulfur atoms in addition to carbonatoms)-amino group), each of R² and R³ is (1) a hydrogen atom, (2) aC₁₋₆ alkyl group which may be substituted by <1> a halogen atom, <2> ahydroxy group which may be substituted by a substituent selected from aC₁₋₆ alkyl, C₁₋₆ alkyl-carbonyl, C₁₋₆ alkylsulfonyl and C₇₋₁₆ aralkyl,<3> an amino group which may be substituted by 1 or 2 C₁₋₆ alkyl, C₁₋₆alkyl-carbonyl and C₆₋₁₄ aryl-carbonyl, <4> a 4- to 10-memberedheterocyclic group containing 1 to 3 heteroatom(s) selected fromnitrogen, oxygen and sulfur atoms in addition to carbon atoms, <5> athio group which may be substituted by C₁₋₆ alkyl, <6> a C₁₋₆alkyl-sulfinyl group or <7> a C₁₋₆ alkyl-sulfonyl group, or (3) a C₁₋₆alkoxy-carbonyl group, R² and R³ may be taken together with the adjacentcarbon atom to form a C₃₋₈ cycloalkane, R⁴ is (i) a hydrogen atom, (ii)a cyano group, (iii) a C₁₋₆ alkyl group [this C₁₋₆ alkyl group may havea substituent selected from (1) a halogen atom, (2) a cyano group, (3) aC₁₋₆ alkoxy group, (4) a hydroxy group, (5) an amino group, (6) amono-C₁₋₆ alkylamino group, (7) a di-C₁₋₆ alkylamino group, (8) atri-C₁₋₆ alkylammonium group, (8) a 4- to 10-membered heterocyclic groupcontaining 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms in addition to carbon atoms which may have an oxo, (9) aC₆₋₁₄ arylthio, (10) an ureido, (11) a carboxy, (12) a carbamoyl, (13) aC₁₋₆ alkoxy-carbonyl, (14) a mono-C₁₋₆ alkyl-carbamoyl, (15) aformylamino and (16) a C₁₋₆ alkyl-carboxamide], (iv) a C₂₋₆ alkenylgroup or (v) a formyl group; X is a bond, oxygen atom, optionallyoxidized sulfur atom, —NH— or —N(methyl)-, R⁵ is, when X is a bond, then(i) a hydrogen atom, (ii) a C₁₋₆ alkyl group or (iii) a halogen atom,when X is an oxygen atom, then (i) a hydrogen atom, (ii) a C₁₋₆ alkylgroup [this C₁₋₆ alkyl group may have a substituent selected from (1) ahalogen atom, (2) a hydroxy group, (3) an amino group, (4) a carboxy,(5) a carbamoyl, (6) a C₁₋₆ alkoxy-carbonyl, (7) a mono-C₁₋₆alkyl-carbamoyl, (8) a di-C₁₋₆ alkyl-carbamoyl, (9) a 4- to 10-memberedheterocyclic group containing 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms in addition to carbon atoms], (iii) aC₂₋₆ alkenyl group [this C₂₋₆ alkenyl group may have a C₆₋₁₄ aryl], (iv)a C₂₋₆ alkynyl group, (v) a C₃₋₆ cycloalkyl group, (vi) a C₇₋₁₆ aralkylgroup, (vii) a C₁₋₆ alkyl-carbonyl group, (viii) a C₆₋₁₄ aryl-carbonylgroup, (ix) a C₁₋₆ alkoxy-carbonyl group, (x) a mono- or di-C₁₋₆alkyl-thiocarbamoyl group, (xi) an optionally halogenated C₁₋₆alkyl-sulfonyl group or (xii) a 4- to 10-membered heterocyclic groupcontaining 1 to 4 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms in addition to carbon atoms [this heterocyclic group mayhave a C₆₋₁₄ aryl], when X is an optionally oxidized sulfur, then (i) aC₁₋₆ alkyl group or (ii) a mono- or di-C₁₋₆ alkyl-carbamoyl group, whenX is —NH— or —N(methyl)-, then (1) a hydrogen atom, (ii) a C₁₋₆ alkylgroup [this C₁₋₆ alkyl group may have a C₁₋₆ alkoxy-carbonyl], (iii)formyl, (iv) a C₁₋₆ alkyl-carbonyl group, (v) a C₁₋₆ alkoxy-carbonylgroup, (vi) a carbamoyl group, (vii) a mono- or di-C₁₋₆ alkyl-carbamoylgroup or (viii) a C₁₋₆ alkyl-sulfonyl group, each of R⁶ and R⁷ is ahydrogen atom or C₁₋₆ alkyl group, R⁶ and R⁷ may be taken together withthe adjacent carbon atom to form a C₃₋₈ cycloalkane, Each of R⁸ and R⁹is a hydrogen atom or a C₁₋₆ alkyl group, Y is <1> a methylene groupwhich may have 1 or 2 C₁₋₆ alkyl or hydroxy group or <2> a carbonylgroup, n is 0 or
 1. 13. The compound according to claim 3, wherein R¹is, (i) a C₆₋₁₄ aryl group which.may have 1 to 3 substituent(s) selectedfrom the following (1) to (20): (1) a halogen atom, (2) a nitro group,(3) a C₁₋₆ alkyl group [this C₁₋₆ alkyl group may have a substituentselected from a halogen atom, cyano, carbamoyl, C₁₋₆ alkyl-carbamoyl,C₁₋₆ alkyl-carbonyloxy, C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkyl-carbamoyl, (5-or 6-membered heterocyclic ring containing 1 to 3 heteroatom(s) selectedfrom nitrogen, sulfur and oxygen atoms in addition to carbon atoms)-C₁₋₆alkyl-carbamoyl, C₁₋₆ alkylsulfonylamino, C₁₋₆ alkoxy-carbonyl andcarboxy], (4) a C₃₋₆ cycloalkyl group, (5) a C₆₋₁₄ aryl group [thisC₆₋₁₄ aryl group may have a substituent selected from amino, optionallyhalogenated C₁₋₆ alkyl-carbonylamino, ureido, C₁₋₆ alkylsulfonylamino,(C₁₋₆ alkyl)(C₁₋₆ alkylsulfonyl) amino, C₁₋₆ alkoxy-carbonyl-C₁₋₆alkylamino], (6) a C₁₋₆ alkoxy group which may have a halogen atom orC₁₋₆ alkoxy-C₆₋₁₄ aryl, (7) a C₆₋₁₄ aryloxy group, (8) a C₁₋₆ alkylthiogroup, (9) a C₁₋₆ alkylsulfinyl group, (10) a C₆₋₁₄ arylthio group, (11)a hydroxy group, (12) a 5- to 14-membered heterocyclic group containing1 to 4 heteroatom(s) selected from nitrogen, sulfur and oxygen atoms[this heterocyclic group may have a substituent selected from oxo,carboxy-C₁₋₆ alkyl, C₁₋₆ alkyl-carbonyloxy-C₁₋₆ alkyl, C₁₋₆alkoxy-carbonyl-C₁₋₆ alkyl, C₁₋₆ alkyl-carbamoyl-C₁₋₆ alkyl], (13) acarboxy group, (14) a group represented by-Formula: —CO—Hal (Hal is ahalogen atom), (15) a C₁₋₆ alkyl-carbonyl group, (16) a C₁₋₆alkyl-sulfonyl group, (17) a C₁₋₆ alkoxy-carbonyl group, (18) asulfamoyl group [this sulfamoyl group may have a substituent selectedfrom C₁₋₆ alkyl, carbamoyl-C₁₋₆ alkyl, (5- or 6-membered heterocyclicring containing 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms in addition to carbon atoms)-C₁₋₆ alkyl], (19) a grouprepresented by Formula: —NR^(a)R^(b) [each of R^(a) and R^(b) is (i) ahydrogen atom, (ii) a C₁₋₆ alkyl, (iii) a (5- or 6-membered heterocyclicring containing 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms in addition to carbon atoms)-C₁₋₆ alkyl, (iv) a C₁₋₆alkoxy-carbonyl-C₁₋₆ alkyl, (v) a di-C₁₋₆alkylamino-methylene-sulfamoyl-C₁₋₆ alkyl, (vi) a carbamoyl-C₁₋₆ alkyl,(vii) a sulfamoyl-C₁₋₆ alkyl, (viii) a C₁₋₆ alkyl-sulfonyl, (ix) a C₁₋₆alkoxy-carbonyl, (x) a di-C₁₋₆ alkoxy-carbonyl-C₂₋₆ alkenyl, (xi) aC₆₋₁₄ aryl, (xii) a 5- or 6-membered heterocyclic group containing 1 to3 heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms [this 5- or 6-membered heterocyclic group mayhave a substituent selected from amino, C₁₋₆ alkyl-carboxamido and C₁₋₆alkyl-sulfonylamino], (xiii) an optionally halogenated C₁₋₆alkyl-carbonyl, (xiv) a C₁₋₆ alkylthio-C₁₋₆ alkyl-carbonyl, (xv) a C₁₋₆alkylsulfinyl-C₁₋₆ alkyl-carbonyl, (xvi) a C₁₋₆ alkylsulfonyl-C₁₋₆alkyl-carbonyl, (xvii) an amino-C₁₋₆ alkyl-carbonyl, (xviii) anoptionally halogenated C₁₋₆ alkyl-carbonyl-amino-C₁₋₆ alkyl-carbonyl,(xix) a C₆₋₁₄ aryl-carbonyl, (xx) a carboxy-C₆₋₁₄ aryl-carbonyl, (xxi)an optionally C₁₋₆ alkyl-esterified phosphono-C₁₋₆ alkyl-C₁₋₆alkyl-C₆₋₁₄ aryl-carbonyl, (xxii) a (5- or 6-membered heterocyclic ringcontaining 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms in addition to carbon atoms)-carbonyl, (xxiii) a (5- or6-membered heterocyclic ring containing 1 to 3 heteroatom(s) selectedfrom nitrogen, sulfur and oxygen atoms in addition to carbon atoms whichmay have a C₁₋₆ alkoxy-carbonyl)-C₁₋₆ alkyl-carbonyl, (xxiv) a C₆₋₁₄aryl-oxy-carbonyl, (xxv) a carboxy-C₁₋₆ alkyl or (xxvi) a carbamoyl],(20) a group represented by Formula: —C(═O)NR^(c)R^(d) [each of R^(c)and R^(d) is (i) a hydrogen atom, (ii) a C₁₋₆ alkyl, (iii) a (5- or6-membered heterocyclic ring containing 1 to 3 heteroatom(s) selectedfrom nitrogen, sulfur and oxygen atoms in addition to carbon atoms)-C₁₋₆alkyl, (iv) a carboxy-C₁₋₆ alkyl, (v) a C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkyl,(vi) a di-C₁₋₆ alkylamino-C₁₋₆ alkyl, (vii) a carbamoyl-C₁₋₆ alkyl,(viii) a C₁₋₆ alkylcarbamoyl-C₁₋₆ alkyl, (ix) a (5- or 6-memberedheterocyclic-group containing 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms)-C₁₋₆ alkyl carbamoyl-C₁₋₆ alkyl, (x)a (5- or 6-membered heterocyclic group containing 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms in addition to carbonatoms)-amino-C₁₋₆ alkyl, (xi) a sulfamoyl-C₆₋₁₄ aryl-C₁₋₆ alkyl, (xii) aC₆₋₁₄ aryl which may have a C₁₋₆ alkoxy, (xiii) a C₁₋₆ alkyl-C₆₋₁₄ arylwhich have an optionally C₁₋₆ alkyl-esterified phosphono group, (xiv) a4- to 10-membered heterocyclic ring containing 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms in addition to carbonatoms [this heterocyclic group may have 1 or 2 substituent(s) selectedfrom a halogen atom, C₁₋₆ alkyl and oxo] or (xv) a C₆₋₁₄aryl-carbamoyl-C₁₋₆ alkyl; (ii) a 5- to 14-membered heterocyclic groupcontaining 1 to 4 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms in addition to carbon atoms which may contain 1 to 3substituent(s) selected from the following (1) to (8): (1) a halogenatom, (2) a C₁₋₆ alkyl group [this alkyl may have a substituent selectedfrom carboxy, C₁₋₆ alkoxy, C₁₋₆ alkoxy-carbonyl, mono-C₁₋₆ alkyl-amino,di-C₁₋₆ alkyl-amino, carbamoyl, C₁₋₆ alkyl-carbamoyl which may have ahydroxy, 4- to 10-membered heterocyclic group containing 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms which may have oxo, (4- to 10-memberedheterocyclic ring containing 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms in addition to carbonatoms)-carbamoyl, carbamoyl-C₁₋₆ alkyl-carbamoyl], (3) a C₁₋₆ alkoxygroup, (4) a C₆₋₁₄ aryl group, (5) a C₇₋₁₆ aralkyl group [this C₇₋₁₆aralkyl group may have a substituent selected from.carboxy, C₁₋₆alkoxy-carbonyl, carbamoyl, C₁₋₆ alkyl-carbamoyl which may have ahydroxy, (4- to 10-membered heterocyclic ring containing 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms)-carbamoyl], (6) a 4- to 10-memberedheterocyclic group containing 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms in addition to carbon atoms (this 4-to 10-membered heterocyclic group may have a substituent selected from aC₁₋₆ alkyl, C₁₋₆ alkoxy-carbonyl, carbamoyl, oxo, 4- to 10-memberedheterocyclic group containing 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms in addition to carbon atoms], (7) anoxo group, (8) an oxide group; (iii) a C₃₋₆ cycloalkyl group; or, (iv) agroup represented by Formula: —L′—R^(1a)′ (L′ is methylene, carbonyl or—NH—, R^(1a) is (1) a hydrogen atom, (2) a C₆₋₁₄ aryl group which mayhave 1 to 5 substituent(s) selected from a C₁₋₆ alkyl and C₁₋₆ alkoxy,(3) a hydroxy group which may be substituted by a C₁₋₆ alkyl group, (4)a C₁₋₆ alkyl-amino group which may be substituted by a 4- to 10-memberedheterocyclic ring containing 1 to 3 heteroatom(s) selected fromnitrogen, oxygen and sulfur atoms in addition to carbon atoms, (6) aC₆₋₁₄ aryl-amino group or (7) a (4- to 10-membered heterocyclic ringcontaining 1 to 3 heteroatom(s) selected from nitrogen, oxygen andsulfur atoms in addition to carbon atoms)-amino group), each of R² andR³ is (1) a hydrogen atom, (2) an optionally halogenated C₁₋₆ alkylgroup or (3) a C₁₋₆ alkoxy-carbonyl group, R2 and R³ may be takentogether with the adjacent carbon atom to form a C₃₋₈ cycloalkane, R⁴ is(i) a hydrogen atom, (ii) a C₁₋₆ alkyl group [this C₁₋₆ alkyl group mayhave a substituent selected from (1) a halogen atom, (2) a cyano group,(3) a C₁₋₆ alkoxy group, (4) a hydroxy group, (5) an amino group, (6) amono-C₁₋₆ alkylamino group, (7) a di-C₁₋₆ alkylamino group, (8) atri-C₁₋₆ alkylammonium group, (9) a 4- to 10-membered heterocyclic groupcontaining 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms in addition to carbon atoms which may have an oxo, (10) aC₆₋₁₄ arylthio, (11) an ureido, (12) a carboxy, (13) a carbamoyl, (14) aC₁₋₆ alkoxy-carbonyl, (15) a mono-C₁₋₆ alkyl-carbamoyl, (16) aformylamino, (17) a C₁₋₆ alkyl-carboxamido] or (iii)-a C₂₋₆ alkenylgroup; X is a bond, oxygen atom, sulfur atom, —NH— or —N(methyl)-, R⁵is, when X is a bond, then (i) a hydrogen atom, (ii) a C₁₋₆ alkyl groupor (iii) a halogen atom, when X is an oxygen atom, then (i) a hydrogenatom, (ii) a C₁₋₆ alkyl group [this C₁₋₆ alkyl group may have asubstituent selected from (1) a halogen atom, (2) a hydroxy group, (3)an amino group, (4) a carboxy, (5) a carbamoyl, (6) a C₁₋₆alkoxy-carbonyl, (7) a mono-C₁₋₆ alkyl-carbamoyl, (8) a di-C₁₋₆alkyl-carbamoyl, (9) a 4- to 10-membered heterocyclic group containing 1to 3 heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms which may have an oxo], (iii) a C₂₋₆ alkenylgroup [this C₂₋₆ alkenyl group may have a C₆₋₁₄ aryl], (iv) a C₂₋₆alkynyl group, (v) a C₃₋₆ cycloalkyl group, (vi) a C₇₋₁₆ aralkyl group,(vii) a C₁₋₆ alkyl-carbonyl group, (viii) a C₆₋₁₄ aryl-carbonyl group,(ix) a C₁₋₆ alkoxy-carbonyl group, (x) a mono- or di-C₁₋₆alkyl-thiocarbamoyl group, (xi) an optionally halogenated C₁₋₆alkyl-sulfonyl group or (xii) a 4-to 10-membered heterocyclic groupcontaining 1 to 4 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms in addition to carbon atoms [this heterocyclic group mayhave a C₆₋₁₄ aryl], when X is a sulfur, then (i) a C₁₋₆ alkyl group or(ii) a mono- or di-C₁₋₆ alkyl-carbamoyl group, when X is —NH— or—N(methyl)-, then (i) a hydrogen atom, (ii) a C₁₋₆ alkyl group [thisC₁₋₆ alkyl group may have a C₁₋₆ alkoxy-carbonyl], (iii) formyl, (iv) aC₁₋₆ alkyl-carbonyl group, (v) a C₁₋₆ alkoxy-carbonyl group, (vi) acarbamoyl group, (vii) a mono- or di-C₁₋₆ alkyl-carbamoyl group or(viii) a C₁₋₆ alkyl-sulfonyl group, each of R⁶ and R⁷ is a hydrogen atomor C₁₋₆ alkyl group, R⁶ and R⁷ may be taken together with the adjacentcarbon atom to form a C₃₋₈ cycloalkane, each of R⁸ and R⁹ is a hydrogenatom or a C₁₋₆ alkyl group, Y is a methylene group which may have ahydroxy group or carbonyl group, n is 0 or
 1. 14. The compound accordingto claim 2, wherein each of R² and R³ is a C₁₋₆ alkyl group.
 15. Thecompound according to claim 2, wherein R⁴ is a hydrogen atom.
 16. Thecompound according to claim 2, wherein each of R⁶ and R⁷ is a C₁₋₆ alkylgroup.
 17. The compound according to claim 2, wherein each of R⁸ and R⁹is a hydrogen atom.
 18. The compound according to claim 2, wherein n is0.
 19. (i)2-(methylsulfinyl)-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]acetamide,(ii)N-(methylsulfonyl)-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]methanesulfonamide,(iii)N-[2-(4-pyridinyl)ethyl]-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide,(iv)N-(2-amino-2-oxoethyl)-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide,(v)N-methyl-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide,(vi)N-ethyl-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide,(vii)N-[3′-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)[1,1′-biphenyl]-3-yl]acetamide,(viii)N-(2-amino-1,1-dimethyl-2-oxoethyl)-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide,(ix)3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-N-methylbenzamide,(x)N-(2-amino-2-oxoethyl)-3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide,(xi)N-(2-amino-1,1-dimethyl-2-oxoethyl)-3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide,(xii)N-[3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]methanesulfonamide,(xiii)N-(hydroxymethyl)-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamideor its salts.
 20. A prodrug of a compound according to claim
 2. 21. Aprocess for producing a compound having a partial structure representedby Formula:

wherein R¹ is defined as described in claim 2, or a salt thereof,comprising: (1) reacting a compound having a partial structurerepresented by Formula:

wherein R¹⁰ is an optionally substituted vinyl group or allyl group, ora salt thereof with a compound represented by Formula: R¹—CN or Formula:R¹—CONH₂ wherein R¹ is defined as described above or a salt thereof, or,(2) reacting a compound having a partial structure represented byFormula:

wherein R¹¹ is an optionally substituted methyl group, Z is anoptionally substituted hydroxy group or halogen atom or a salt thereofwith a compound represented by Formula: R¹—CN wherein R¹ is defined asdescribed above or a salt thereof.
 22. A process for producing acompound according to claim 2, comprising: reacting a compoundrepresented by Formula:

wherein each symbol is defined as described in claim 2 or a salt thereofwith a compound represented by Formula: R¹—CN or Formula: R¹—CONH₂wherein R¹ is defined as described in claim 2 or a salt thereof, or,reacting a compound represented by Formula:

wherein Z is an optionally substituted hydroxy group or halogen atom,and other symbols are defined as described in claim 2 or a salt thereofwith a compound represented by Formula: R¹—CN wherein R¹ is defined asdescribed in claim 2 or a salt thereof.
 23. A phosphodiesterase IVinhibitor comprising a compound having a partial structure representedby Formula:

wherein — — — is a single bond or double bond or a salt thereof.
 24. Apharmaceutical composition comprising a compound according to claim 1 ora salt thereof.
 25. A pharmaceutical composition comprising a compoundaccording to claim 2 or a salt or prodrug thereof.
 26. Thepharmaceutical composition according to claim 24 or 25, which is aphosphodiesterase IV inhibitor.
 27. The pharmaceutical compositionaccording to claims 23 to 26, which is a prophylactic or therapeuticagent against inflammatory diseases.
 28. The pharmaceutical compositionaccording to claims 23 to 26, which is a prophylactic or therapeuticagent against asthma, chronic obstructive pulmonary disease (COPD),rheumatoid arthritis, autoimmune disease or diabetes.
 29. Apharmaceutical comprising (1) a compound having a partial structurerepresented by Formula:

wherein — — — is a single bond or double bond or a salt thereof incombination with (2) a drug selected from antiasthma agents,antiallergic agents, anticholinergic agents, antiinflammatory agents,antibacterial agents, antifungal agents and antidiabetic agents.
 30. Apharmaceutical comprising (1) a compound according to claim 1 or a saltthereof in combination with (2) a drug selected from antiasthma agents,antiallergic agents, anticholinergic agents, antiinflammatory agents,antibacterial agents, antifungal agents and antidiabetic agents.
 31. Apharmaceutical comprising (1) a compound according to claim 2, or a saltor prodrug thereof in combination with (2) a drug selected fromantiasthma agents, antiallergic agents, anticholinergic agents,antiinflammatory agents, antibacterial agents, antifungal agents andantidiabetic agents.
 32. The pharmaceutical according to claims 29 to31, which is a prophylactic or therapeutic agent against inflammatorydiseases.
 33. The pharmaceutical according to claims 29 to 31, which isa prophylactic or therapeutic agent against asthma, chronic obstructivepulmonary disease (COPD), rheumatoid arthritis, autoimmune disease ordiabetes.
 34. Escherichia coli BL21/pPDE4D3 (FERM BP-7075).
 35. A methodfor inhibiting a phosphodiesterase IV comprising administering aneffective amount of a compound having a partial structure represented byFormula:

wherein — — — is a single bond or double bond or a salt thereof to amammal.
 36. A method for preventing or treating inflammatory diseasescomprising administering an effective amount of a compound having apartial structure represented by Formula:

wherein — — — is a single bond or double bond or a salt thereof to amammal.
 37. A method for preventing or treating asthma, chronicobstructive pulmonary disease (COPD), rheumatoid arthritis, autoimmunedisease or diabetes comprising administering an effective amount of acompound having a partial structure represented by Formula:

wherein — — — is a single bond or double bond or a salt thereof to amammal.
 38. A method for inhibiting a phosphodiesterase IV comprisingadministering an effective amount of the compound according to claim 1or a salt thereof to a mammal.
 39. A method for preventing or treatinginflammatory diseases comprising administering an effective amount ofthe compound according to claim 1 or a salt thereof to a mammal.
 40. Amethod for preventing or treating asthma, chronic obstructive pulmonarydisease (COPD), rheumatoid arthritis, autoimmune disease or diabetescomprising administering an effective amount of the compound accordingto claim 1 or a salt thereof to a mammal.
 41. A method for inhibiting aphosphodiesterase IV comprising administering an effective amount of thecompound according to claim 2 or a salt or prodrug thereof to a mammal.42. A method for preventing or treating inflammatory diseases comprisingadministering an effective amount of the compound according to claim 2or a salt or prodrug thereof to a mammal.
 43. A method for preventing ortreating asthma, chronic obstructive pulmonary disease (COPD),rheumatoid arthritis, autoimmune disease or diabetes comprisingadministering an effective amount of the compound according to claim 2or a salt or prodrug thereof to a mammal.
 44. A method for preventing ortreating inflammatory diseases comprising administering (1) an effectiveamount of a compound having a partial structure represented by Formula:

wherein — — — is a single bond or double bond or a salt thereof incombination with (2) an effective amount of a drug selected fromantiasthma agents, antiallergic agents, anticholinergic agents,antiinflammatory agents, antibacterial agents, antifungal agents andantidiabetic agents to a mammal.
 45. A method for preventing or treatingasthma, chronic obstructive pulmonary disease (COPD), rheumatoidarthritis, autoimmune disease or diabetes comprising administering (1)an effective amount of a compound having a partial structure representedby Formula:

wherein — — — is a single bond or double bond, or a salt thereof incombination with (2) an effective amount of a drug selected fromantiasthma agents, antiallergic agents, anticholinergic agents,antiinflammatory agents, antibacterial agents, antifungal agents andantidiabetic agents to a mammal.
 46. A method for preventing or treatinginflammatory diseases comprising administering (1) an effective amountof the compound according to claim 1 or a salt thereof in combinationwith (2) an effective amount of a drug selected from antiasthma agents,antiallergic agents, anticholinergic agents, antiinflammatory agents,antibacterial agents, antifungal agents and antidiabetic agents to amammal.
 47. A method for preventing or treating asthma, chronicobstructive pulmonary disease (COPD), rheumatoid arthritis, autoimmunedisease or diabetes comprising administering (1) an effective amount ofthe compound according to claim 1 or a salt thereof in combination with(2) an effective amount of a drug selected from antiasthma agents,antiallergic agents, anticholinergic agents, antiinflammatory agents,antibacterial agents, antifungal agents and antidiabetic agents to amammal.
 48. A method for preventing or treating inflammatory diseasescomprising administering (1) an effective amount of the compoundaccording to claim 2 or a salt or prodrug thereof in combination with(2) an effective amount of a drug selected from antiasthma agents,antiallergic agents, anticholinergic agents, antiinflammatory agents,antibacterial agents, antifungal agents and antidiabetic agents to amammal.
 49. A method for preventing or treating asthma, chronicobstructive pulmonary disease (COPD), rheumatoid arthritis, autoimmunedisease or diabetes comprising administering (1) an effective amount ofthe compound according to claim 2 or a salt or prodrug thereof incombination with (2) an effective amount of a drug selected fromantiasthma agents, antiallergic agents, anticholinergic agents,antiinflammatory agents, antibacterial agents, antifungal agents andantidiabetic agents to a mammal.
 50. A use of a compound having apartial structure represented by Formula:

wherein — — — is a single bond or double bond, or a salt thereof forproducing a phosphodiesterase IV inhibitor.
 51. A use of a compoundhaving a partial structure represented by Formula:

wherein — — — is a single bond or double bond, or a salt thereof forproducing a prophylactic or therapeutic agent against inflammatorydiseases.
 52. A use of a compound having a partial structure representedby Formula:

wherein — — — is a single bond or double bond, or a salt thereof forproducing a prophylactic or therapeutic agent against asthma, chronicobstructive pulmonary disease (COPD), rheumatoid arthritis, autoimmunedisease or diabetes.
 53. A use of the compound according to claim 1 or asalt thereof for producing a phosphodiesterase IV inhibitor.
 54. A useof the compound according to claim 1 or a salt thereof for producing aprophylactic or therapeutic agent against inflammatory diseases.
 55. Ause of the compound according to claim 1 or a salt thereof for producinga prophylactic or therapeutic agent against asthma, chronic obstructivepulmonary disease (COPD), rheumatoid arthritis, autoimmune disease ordiabetes.
 56. A use of the compound according to claim 2 or a salt orprodrug thereof for producing a phosphodiesterase IV inhibitor.
 57. Ause of the compound according to claim 2 or a salt or prodrug thereoffor producing a prophylactic or therapeutic agent against inflammatorydiseases.
 58. A use of the compound according to claim 2 or a salt orprodrug thereof for producing a prophylactic or therapeutic agentagainst asthma, chronic obstructive pulmonary disease (COPD), rheumatoidarthritis, autoimmune disease or diabetes.
 59. A compound represented byFormula:

wherein each of R^(2a) and R^(3a) is an optionally substituted aliphatichydrocarbon group or acyl group, R^(4a) is a hydrogen atom, optionallysubstituted hydrocarbon group, acyl group or optionally substitutedhydroxy group, R^(5a) is an optionally substituted hydrocarbon group,acyl group, optionally substituted heterocyclic group or halogen atom,Each of R^(6a), R^(7a), R^(8a) and R^(9a) is a hydrogen atom oroptionally substituted hydrocarbon group, X^(a) is a bond, oxygen atom,optionally oxidized sulfur atom or optionally substituted nitrogen atom,or by Formula:

wherein each of R^(2a) and R^(3a) is an optionally substituted aliphatichydrocarbon group or acyl group, R^(4a) is a hydrogen atom, optionallysubstituted hydrocarbon group, acyl group or optionally substitutedhydroxy group, R^(4a) is an optionally substituted hydrocarbon group,acyl group, optionally substituted heterocyclic.group or halogen atom,Each of R^(6a), R^(7a), R^(8a) and R^(9a) is a hydrogen atom oroptionally substituted hydrocarbon group, X^(a) is a bond, oxygen atom,optionally oxidized sulfur atom or optionally substituted nitrogen atom,Z is an optionally substituted hydroxy group or halogen atom, or a saltthereof.
 60. The compound according to claim 59, wherein each of R^(2a)and R^(3a) is any of the following (i) to (ii): (i) a C₁₋₆ alkyl groupor C₃₋₆ cycloalkyl group which may have 1 to 5 substituent(s) selectedfrom the group (hereinafter referred to as Substituent Group B)consisting of (1) a halogen atom, (2) a C₁₋₃ alkylenedioxy group, (3) anitro group, (4) an optionally halogenated C₁₋₆ alkyl group, (5) a C₃₋₆cycloalkyl group, (6) a C₆₋₁₄ aryl group, (7) an optionally halogenatedC₁₋₆ alkoxy group, (8) an optionally halogenated C₁₋₆ alkylthio group,(9) a hydroxy group, (10) an amino group, (11) a mono-C₁₋₆ alkylaminogroup, (12) a mono-C₆₋₁₄ arylamino group, (13) a di-C₁₋₆ alkylaminogroup, (14) a di-C₆₋₁₄ arylamino group, (15) an acyl -group selectedfrom formyl, carboxy, carbamoyl, C₁₋₆ alkyl-carbonyl, C₃₋₆cycloalkyl-carbonyl, C₁₋₆ alkoxy-carbonyl, C₆₋₁₄ aryl-carbonyl, C₇₋₁₆aralkyl-carbonyl, C₆₋₁₄ aryloxy-carbonyl, C₇₋₁₆ aralkyloxy-carbonyl, (5-or 6-membered heterocycle having, in addition to carbon atoms, 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygen atoms)-carbonyl,mono-C₁₋₆ alkyl-carbamoyl, di-C₁₋₆ alkyl carbamoyl, C₆₋₁₄aryl-carbamoyl, (5- or 6-membered heterocycle having, in addition tocarbon atoms, 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms)-carbamoyl, C₁₋₆ alkyl-thiocarbonyl, C₃₋₆cycloalkyl-thiocarbonyl, C₁₋₆ alkoxy-thiocarbonyl, C₆₋₁₄aryl-thiocarbonyl, C₇₋₁₆ aralkyl-thiocarbonyl, C₆₋₁₄aryloxy-thiocarbonyl, C₇₋₁₆ aralkyloxy-thiocarbonyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbonyl,thiocarbamoyl, mono-C₁₋₆ alkyl-thiocarbamoyl, di-C₁₋₆alkyl-thiocarbamoyl, C₆₋₁₄ aryl-thiocarbamoyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbamoyl,mono-C₁₋₆ alkylsulfamoyl, di-C₁₋₆ alkylsulfamoyl, C₆₋₁₄ arylsulfamoyl,C₁₋₆ alkylsulfonyl, C₆₋₁₄ arylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₄arylsulfinyl, sulfino, sulfo, C₁₋₆ alkoxysulfinyl, C₆₋₁₄aryloxysulfinyl, C₁₋₆ alkoxysulfonyl and C₆₋₁₄ aryloxysulfonyl, (16) anacylamino group selected from formylamino, C₁₋₆ alkyl-carboxamido, C₆₋₁₄aryl-carboxamido, C₁₋₆ alkoxy-carboxamido, C₁₋₆ alkylsulfonylamino andC₆₋₁₄ arylsulfonylamino, (17) an acyloxy group selected from C₁₋₆alkyl-carbonyloxy, C₆₋₁₄ aryl-carbonyloxy, C₁₋₆ alkoxy-carbonyloxy,mono-C₁₋₆ alkyl-carbamoyloxy, di-C₁₋₆ alkyl-carbamoyloxy, C₆₋₁₄aryl-carbamoyloxy and nicotinoyloxy, (18) a 4- to 14-memberedheterocyclic group 30 having, in addition to carbon atoms, 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygen atoms, (19) aphosphono group, (20) a C₆₋₁₄ aryloxy group, (21) a di-C₁₋₆alkoxy-phosphoryl group, (22) a C₆₋₁₄ arylthio group, (23) a hydrazinogroup, (24) an imino group, (25) an oxo group, (26) an ureido group,(27) a C₁₋₆ alkyl-ureido group, (28) a di-C₁₋₆-alkyl-ureido group, (29)an oxide group and (30) a group formed by binding 2 or 3 groups selectedfrom (1) to (29) listed above, (ii) an acyl group selected from formyl,carboxy, carbamoyl, C₁₋₆ alkyl-carbonyl, C₃₋₆ cycloalkyl-carbonyl C₁₋₆alkoxy-carbonyl, C₆₋₁₄ aryl-carbonyl, C₇₋₁₆ aralkyl-carbonyl, C₆₋₁₄aryloxy-carbonyl, C₇₋₁₆ aralkyloxy-carbonyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-carbonyl, mono-C₁₋₆alkyl-carbamoyl, di-C₁₋₆ alkyl carbamoyl, C₆₋₁₄ aryl-carbamoyl, (5- or6-membered heterocycle having, in addition to carbon atoms, 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygenatoms)-carbamoyl, C₁₋₆ alkyl-thiocarbonyl, C₃₋₆ cycloalkyl-thiocarbonyl,C₁₋₆ alkoxy-thiocarbonyl, C₆₋₁₄ aryl-thiocarbonyl, C₇₋₁₆aralkyl-thiocarbonyl, C₆₋₁₄ aryloxy-thiocarbonyl, C₇₋₁₆aralkyloxy-thiocarbonyl, (5- or 6-membered heterocycle.,having, inaddition to carbon atoms, 1 to 3-heteroatom(s) selected from nitrogen,sulfur and oxygen atoms)-thiocarbonyl, thiocarbamoyl, mono-C₁₋₆alkyl-thiocarbamoyl, di-C₁₋₆ alkyl-thiocarbamoyl, C₆₋₁₄aryl-thiocarbamoyl, (5- or 6-membered heterocycle having, in addition tocarbon atoms, 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms)-thiocarbamoyl, mono-C₁₋₆ alkylsulfamoyl, di-C₁₋₆alkylsulfamoyl, C₆₋₁₄ arylsulfamoyl, C₁₋₆ alkylsulfonyl, C₆₋₁₄arylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₄ arylsulfinyl, sulfino, sulfo,C₁₋₆ alkoxysulfinyl C₆₋₁₄ aryloxysulfinyl, C₁₋₆ alkoxysulfonyl and C₆₋₁₄aryloxysulfonyl, which may have 1 to 5 substituent(s) selected fromSubstituent Group B described above; R^(4a) is (i) a hydrogen atom, (ii)a C₁₋₆ alkyl group, C₃₋₆ cycloalkyl group, C₆₋₁₄ aryl group or C₇₋₁₆aralkyl group which may have 1 to 5 substituent(s) selected fromSubstituent Group B described above, (iii) an acyl group selected fromformyl, carboxy, carbamoyl, C₁₋₆ alkyl-carbonyl, C₃₋₆cycloalkyl-carbonyl, C₁₋₆ alkoxy-carbonyl, C₆₋₁₄ aryl-carbonyl, C₇₋₁₆aralkyl-carbonyl, C₆₋₁₄ aryloxy carbonyl, C₇₋₁₆ aralkyloxy-carbonyl, (5-or 6-membered heterocycle having, in addition to carbon atoms, 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygen atoms)-carbonyl,mono-C₁₋₆ alkyl-carbamoyl, di-C₁₋₆ alkyl-carbamoyl, C₆₋₁₄aryl-carbamoyl, (5- or 6-membered heterocycle having, in addition tocarbon atoms, 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms)-carbamoyl, C₁₋₆ alkyl-thiocarbonyl, C₃₋₆cycloalkyl-thiocarbonyl, C₁₋₆ alkoxy-thiocarbonyl, C₆₋₁₄aryl-thiocarbonyl, C₇₋₁₆ aralkyl-thiocarbonyl, C₆₋₁₄aryloxy-thiocarbonyl, C₇₋₁₆ aralkyloxy-thiocarbonyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbonyl,thiocarbamoyl, mono-C₁₋₆ alkyl-thiocarbamoyl, di-C₁₋₆alkyl-thiocarbamoyl, C₆t₁₄ aryl-thiocarbamoyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbamoyl,mono-C₁₋₆ alkylsulfamoyl, di-C₁₋₆ alkylsulfamoyl, C₆₋₁₄ arylsulfamoyl,C₁₋₆ alkylsulfonyl, C₆₋₁₄ arylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₄arylsulfinyl, sulfino, sulfo, C₁₋₆ alkoxysulfinyl, C₆₋₁₄aryloxysulfinyl, C₁₋₆ alkoxysulfonyl and C₆₋₁₄ aryloxysulfonyl, whichmay have 1 to 5 substituent(s) selected from Substituent Group Bdescribed above; (iv) a group represented by Formula: —OR^(4a)′ (whereinR^(4a)′ is <1> a hydrogen atom, <2> a C₁₋₆ alkyl group, C₃₋₆ cycloalkylgroup, C₆₋₁₄ aryl group or C₇₋₁₆ aralkyl group which may have 1 to 5substituent(s) selected from Substituent Group B-described above, or, 3>an acyl group selected from formyl, carboxy, carbamoyl, C₁₋₆alkyl-carbonyl, C₃₋₆ cycloalkyl-carbonyl C₁₋₆ alkoxy-carbonyl, C₆₋₁₄aryl-carbonyl, C₇₋₁₆ aralkyl-carbonyl, C₆₋₁₄ aryloxy-carbonyl, C₇₋₁₆aralkyloxy-carbonyl, a (5- or 6-membered heterocycle having, in additionto carbon atoms, 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms)-carbonyl, mono-C₁₋₆ alkyl-carbamoyl. di-C₁₋₆alkyl-carbamoyl, C₆₋₁₄ aryl-carbamoyl, (5- or 6-membered heterocyclehaving, in addition to carbon atoms, 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms)-carbamoyl, C₁₋₆ alkyl-thiocarbonyl,C₃₋₆ cycloalkyl-thiocarbonyl, C₁₋₆ alkoxy-thiocarbonyl, C₆₋₁₄aryl-thiocarbonyl, C₇₋₁₆ aralkyl-thiocarbonyl, C₆₋₁₄aryloxy-thiocarbonyl, C₇₋₁₆ aralkyloxy-thiocarbonyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbonyl,thiocarbamoyl, mono-C₁₋₆ alkyl-thiocarbamoyl, di-C₁₋₆alkyl-thiocarbamoyl, C₆₋₁₄ aryl-thiocarbamoyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbamoyl,mono-C₁₋₆ alkylsulfamoyl, di-C₁₋₆ alkylsulfamoyl, C₆₋₁₄ arylsulfamoyl,C₁₋₆ alkylsulfonyl, C₆₋₁₄ arylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₄arylsulfinyl, sulfino, sulfo, C₁₋₆ alkoxysulfinyl, C₆₋₁₄aryloxysulfinyl, C₁₋₆ alkoxysulfonyl and C₆₋₁₄ aryloxysulfonyl, whichmay have 1 to 5 substituent(s) selected from Substituent Group Bdescribed above); R⁵ is any of the following (i) to (iv): (i) a C₁₋₆alkyl group, C₃₋₆ cycloalkyl group, C₆₋₁₄ aryl group or C₇₋₁₆ aralkylgroup which may have 1 to 5 substituent(s) selected from SubstituentGroup B described above, (ii) an acyl group selected from formyl,carboxy, carbamoyl, C₁₋₆ alkyl-carbonyl, C₃₋₆ cycloalkyl-carbonyl, C₁₋₆alkoxy-carbonyl, C₆₋₁₄ aryl-carbonyl, C₇₋₁₆ aralkyl-carbonyl, C₆₋₁₄aryloxy-carbonyl, C₇₋₁₆ aralkyloxy-carbonyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-carbonyl, mono-C₁₋₆alkyl-carbamoyl, di-C₁₋₆ alkyl-carbamoyl, C₆₋₁₄ aryl-carbamoyl, (5- or6-membered heterocycle having, in addition to carbon atoms, 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygenatoms)-carbamoyl, C₁₋₆ alkyl-thiocarbonyl, C₃₋₆ cycloalkyl-thiocarbonyl.C₁₋₆ alkoxy-thiocarbonyl, C₆₋₁₄ aryl-thiocarbonyl, C₇₋₁₆aralkyl-thiocarbonyl, C₆₋₁₄ aryloxy-thiocarbonyl, C₇₋₁₆aralkyloxy-thiocarbonyl, (5- or 6-membered heterocycle having, inaddition to carbon atoms, 1 to 3 heteroatom(s) selected from nitrogen,sulfur and oxygen atoms)-thiocarbonyl, thiocarbamoyl, mono-C₁₋₆alkyl-thiocarbamoyl, di-C₁₋₆ alkyl-thiocarbamoyl, C₆₋₁₄aryl-thiocarbamoyl, (5- or 6-membered heterocycle having, in addition tocarbon atoms, 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms)-thiocarbamoyl, mono-C₁₋₆ alkylsulfamoyl, di-C₁₋₆alkylsulfamoyl, C₆₋₁₄ arylsulfamoyl, C₁₋₆ alkylsulfonyl, C₆₋₁₄arylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₄ arylsulfinyl, sulfino, sulfo,C₁₋₆ alkoxysulfinyl, C₆₋₁₄ aryloxysulfinyl, C₁₋₆ alkoxysulfonyl andC₆₋₁₄ aryloxysulfonyl, which may have 1 to 5 substituent(s) selectedfrom Substituent Group B described above, (iii) a 5- to 14-memberedheterocyclic ring containing 1 to 4 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms in addition to carbon atoms which maycontain 1 to 5 substituent(s) selected from Substituent Group Bdescribed above, (iv) a halogen atom; each of R^(6a), R^(7a), R^(8a) andR^(9a) is (i) a hydrogen atom or (ii) a C₁₋₆ alkyl group, C₃₋₆cycloalkyl group, C₆₋₁₄ aryl group or C₇₋₁₆ aralkyl group which may have1 to 5 substituent(s) selected from Substituent Group B described above,X^(a) is (i) a bond, (ii) an oxygen atom, (iii) an optionally oxidizedsulfur atom, (iv) a nitrogen atom which may have a C₁₋₆ alkyl group,C₂₋₆ alkenyl group, C₂₋₆ alkynyl group, C₃₋₆ cycloalkyl group, C₃₋₆cycloalkenyl group, C₆₋₁₄ aryl group or C₇₋₁₆ aralkyl group which mayhave 1 to 5 substituent(s) selected from Substituent Group B describedabove, (v) a nitrogen atom having.an acyl group selected from formyl,carboxy, carbamoyl, C₁₋₆ alkyl-carbonyl. C₃₋₆ cycloalkyl-carbonyl, C₁₋₆alkoxy-carbonyl, C₆₋₁₄ aryl-carbonyl, C₇₋₁₆ aralkyl-carbonyl, C₆₋₁₄aryloxy carbonyl, C₇₋₁₆ aralkyloxy-carbonyl, (5- or 6-memberedheterocycle having, in addition.to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-carbonyl, mono-C₁₋₆alkyl-carbamoyl, di-C₁₋₆ alkyl-carbamoyl, C₆₋₁₄ aryl-carbamoyl, (5- or6-membered heterocycle having, in addition to carbon atoms, 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygenatoms)-carbamoyl, C₁₋₆ alkyl-thiocarbonyl, C₃₋₆ cycloalkyl-thiocarbonyl,C₁₋₆ alkoxy-thiocarbonyl, C₆₋₁₄ aryl-thiocarbonyl, C₇₋₁₆aralkyl-thiocarbonyl, C₆₋₁₄ aryloxy-thiocarbonyl, C₇₋₁₆aralkyloxy-thiocarbonyl, (5- or 6-membered heterocycle having, Inaddition to carbon atoms, 1 to 3 heteroatom(s) selected from nitrogen,sulfur and oxygen atoms)-thiocarbonyl, thiocarbamoyl, mono-C₁₋₆alkyl-thiocarbamoyl, di-C₁₋₆ alkyl-thiocarbamoyl, C₆₋₁₄aryl-thiocarbamoyl, (5- or 6-membered heterocycle having, in addition tocarbon atoms, 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms)-thiocarbamoyl, mono-C₁₋₆ alkylsulfamoyl, di-C₁₋₆alkylsulfamoyl, C₆₋₁₄ arylsulfamoyl, C₁₋₆ alkylsulfonyl, C₆₋₁₄arylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₄ arylsulfinyl, sulfino, sulfo,C₁₋₆ alkoxysulfinyl, C₆₋₁₄ aryloxysulfinyl, C₁₋₆ alkoxysulfonyl andC₆₋₁₄ aryloxysulfonyl, which may have 1 to 5 substituent(s) selectedfrom Substituent Group B described above, or, (vi) a nitrogen atomhaving a 5- to 14-membered heterocyclic group containing 1 to 4heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms which may contain 1 to 5 substituent(s)selected from Substituent Group B described above; Z is (i) a grouprepresented by Formula: —OZ^(a) (Z^(a) is <1> a hydrogen atom, <2> aC₁₋₆ alkyl group, C₂₋₆ alkenyl group, C₂₋₆ alkynyl group, C₃₋₆cycloalkyl group, C₃₋₆ cycloalkenyl group, C₆₋₁₄ aryl group or C₇₋₁₆aralkyl group which may have 1 to 5 substituent(s) selected fromSubstituent Group B described above, or, <3> an acyl group selected fromformyl, carboxy, carbamoyl, C₁₋₆ alkyl-carbonyl, C₃₋₆cycloalkyl-carbonyl, C₁₋₆ alkoxy-carbonyl, C₆₋₁₄ aryl-carbonyl, C₇₋₁₆aralkyl-carbonyl, C₆₋₁₄ aryloxy-carbonyl, C₇₋₁₆ aralkyloxy-carbonyl, (5-or 6-membered heterocycle having, in addition to carbon atoms, 1 to 3heteroatom(s) selected from nitrogen sulfur and oxygen atoms)-carbonyl,mono-C₁₋₆ alkyl-carbamoyl, di-C₁₋₆ alkyl carbamoyl, C₆₋₁₄aryl-carbamoyl, (5- or 6-membered heterocycle having, in addition tocarbon atoms, 1 to 3 heteroatom(s) selected from nitrogen, sulfur andoxygen atoms)-carbamoyl, C₁₋₆ alkyl-thiocarbonyl, C₃₋₆cycloalkyl-thiocarbonyl, C₁₋₆ alkoxy-thiocarbonyl, C₆₋₁₄aryl-thiocarbonyl, C₇₋₁₆ aralkyl-thiocarbonyl, C₆₋₁₄aryloxy-thiocarbonyl, C₇₋₁₆ aralkyloxy-thiocarbonyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbonyl,thiocarbamoyl, mono-C₁₋₆ alkyl-thiocarbamoyl, di-C₁₋₆alkyl-thiocarbamoyl, C₆₋₁₄ aryl-thiocarbamoyl, (5- or 6-memberedheterocycle having, in addition to carbon atoms, 1 to 3 heteroatom(s)selected from nitrogen, sulfur and oxygen atoms)-thiocarbamoyl,mono-C₁₋₆ alkylsulfamoyl, di-C₁₋₆ alkylsulfamoyl, C₆₋₁₄ arylsulfamoyl,C₁₋₆ alkylsulfonyl, C₆₋₁₄ arylsulfonyl, C₁₋₆ -alkylsulfinyl, C₆₋₁₄arylsulfinyl, sulfino, sulfo, C₁₋₆ alkoxysulfinyl, C₆₋₁₄aryloxysulfinyl; C₁₋₆ alkoxysulfonyl and C₆₋₁₄ aryloxysulfonyl, whichmay have 1 to 5 substituent(s) selected from Substituent Group Adescribed above) or (ii), a halogen atom group.
 61. The compoundaccording to claim 59, wherein each of R^(2a) and R^(3a) is (1) a C₁₋₆alkyl group which may be substituted by <1> a halogen atom, <2> ahydroxy group which may be substituted by a substituent selected from aC₁₋₆ alkyl, C₁₋₆ alkyl-carbonyl, C₁₋₆ alkylsulfonyl and C₇₋₁₆ aralkyl,<3> an amino group which may be substituted by 1 or 2 C₁₋₆ alkyl, C₁₋₆alkyl-carbonyl and C₆₋₁₄ aryl-carbonyl, <4> a 4- to 10-memberedheterocyclic group containing 1 to 3 heteroatom(s) selected fromnitrogen, oxygen and sulfur atoms in addition to carbon atoms, <5> athio group which may be substituted by C₁₋₆ alkyl, <6> a C₁₋₆alkyl-sulfinyl group or <7> a CI₆ alkyl-sulfonyl group or (2) a C₁₋₆alkoxy-carbonyl group, R^(4a) is (i) a hydrogen atom, (ii) a C₁₋₆ alkylgroup [this C₁₋₆ alkyl group may have a substituent selected from (1) ahalogen atom, (2) a C₁₋₆ alkoxy group, (3) a hydroxy group, (4) an aminogroup, (5) a mono-C₁₋₆ alkylamino group, (6) a di-C₁₋₆ alkylamino group,(7) a 4- to 10-membered heterocyclic group containing 1 to 3heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms which may have an oxo, (8) a C₆₋₁₄ arylthio,(9) an ureido, (10) a carboxy, (11) a carbamoyl, (12) a C₁₋₆alkoxy-carbonyl, (13) a mono-C₁₋₆ alkyl-carbamoyl, (14) a formylaminoand (15) a C₁₋₆ alkyl-carboxamido] or (iii) a formyl group; X^(a) is abond, oxygen atom, optionally oxidized sulfur atom, —NH— or —N(methyl)-,R^(5a) is, when X^(a) is a bond, then (i) a C₁₋₆ alkyl group or (ii) ahalogen atom, when X^(a) is an oxygen atom, then (i) a C₁₋₆ alkyl group[this C₁₋₆ alkyl group may have a substituent selected from (1) ahalogen atom, (2) a hydroxy group, (3) an amino group, (4) a carboxy,(5) a carbamoyl, (6) a C₁₋₆ alkoxy-carbonyl, (7) a mono-C₁₋₆alkyl-carbamoyl, (8) a di-C₁₋₆ alkyl-carbamoyl, (9) a 4- to 10-memberedheterocyclic group containing 1 to 3 heteroatom(s) selected fromnitrogen, sulfur and oxygen atoms in addition to carbon atoms], (ii) aC₃₋₆ cycloalkyl group, (iii) a C₇₋₁₆ aralkyl group, (iv) a C₁₋₆alkyl-carbonyl group, (v) a C₆₋₁₄ aryl-carbonyl group, (vi) a C₁₋₆alkoxy-carbonyl group, (vii) a mono- or di-C₁₋₆ alkyl-thiocarbamoylgroup, (viii) an optionally halogenated C₁₋₆ alkyl-sulfonyl group or(ix) a 4- to 10-membered heterocyclic group containing 1 to 4heteroatom(s) selected from nitrogen, sulfur and oxygen atoms inaddition to carbon atoms [this heterocyclic group may have a C₆₋₁₄aryl], when X^(a) is an optionally oxidized sulfur, then (i) a C₁₋₆alkyl group or (ii) a mono- or di-C₁₋₆ alkyl-carbamoyl group, when X^(a)is —NH— or —N(methyl)-, then (i) a C₁₋₆ alkyl group [this C₁₋₆ alkylgroup may have a C₁₋₆ alkoxy-carbonyl], (ii) formyl, (iii) a C₁₋₆alkyl-carbonyl group, (iv) a C₁₋₆ alkoxy-carbonyl group, (v) a carbamoylgroup, (vi) a mono- or di-C₁₋₆ alkyl-carbamoyl group or (vii) a C₁₋₆alkyl-sulfonyl group, each of R^(6a), R^(7a), R^(8a) and R^(9a) is ahydrogen atom or C₁₋₆ alkyl group, Z is (i) a hydroxy group which may besubstituted by a C₁₋₆ alkyl-carbonyl or (ii) a halogen atom.
 62. A useof the compound according to claim 59 or a salt thereof for producingthe compound according to claim 2 or a salt thereof.